‘PUFA–GPR40–CREB signaling’ hypothesis for the adult primate neurogenesis

‘PUFA–GPR40–CREB signaling’ hypothesis for the adult primate neurogenesis

Progress in Lipid Research 51 (2012) 221–231 Contents lists available at SciVerse ScienceDirect Progress in Lipid Research journal homepage: www.els...

2MB Sizes 0 Downloads 12 Views

Progress in Lipid Research 51 (2012) 221–231

Contents lists available at SciVerse ScienceDirect

Progress in Lipid Research journal homepage: www.elsevier.com/locate/plipres

Review

‘PUFA–GPR40–CREB signaling’ hypothesis for the adult primate neurogenesis Tetsumori Yamashima ⇑ Department of Restorative Neurosurgery, Kanazawa University Graduate School of Medical Science, Takara-machi 13-1, Kanazawa 920-8641, Japan

a r t i c l e

i n f o

a b s t r a c t

Article history: Available online 17 February 2012

Despite the well-known effects of polyunsaturated fatty acids (PUFA) on synaptic plasticity, PUFA-modulated signaling mechanism is unknown especially in humans. In 2003, three groups reported that G protein-coupled receptor 40 (GPR40) induces Ca2+ mobilization in response to PUFA. Although GPR40 gene is abundantly expressed in the primate brain, it is negligible in the rodent brain. Diverse PUFA including docosahexaenoic acid (DHA) are in vitro ligands for GPR40, but nobody knows its downstream pathway. cAMP-response element binding protein (CREB) is a transcription factor transmitting extracellular signals to change gene expression. Although PUFA, transported by fatty acid binding proteins (FABP), directly phosphorylate CREB in rodents, hydrophobic PUFA cannot access to the nuclei in the primate neurons because of lack of a cargo protein. Ischemia-enhanced adult neurogenesis in monkeys showed concomitant upregulation of GPR40 and phosphorylated CREB, and localization of both in the neurogenic niche. Here, ‘PUFA–GPR40–CREB signaling’ hypothesis was highlighted as a regulator of adult neurogenesis specific for primates. Ó 2012 Elsevier Ltd. All rights reserved.

Keywords: Adult neurogenesis Hippocampus Primate PUFA GPR40 CREB BDNF

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction . . . . . . . . PUFA . . . . . . . . . . . . . . FABP . . . . . . . . . . . . . . GPR40 . . . . . . . . . . . . . CREB . . . . . . . . . . . . . . BDNF and PSA–NCAM Concluding remarks . . Acknowledgments . . . References . . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

222 222 224 224 226 228 229 229 229

Abbreviations: AC, adenylyl cyclase; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ARA, arachidonic acid; BDNF, brain-derived neurotrophic factor; BrdU, bromodeoxyuridine; [Ca2+]i, intracellular Ca2+ concentration; CaMK, calmodulin-dependent kinase; cAMP, cyclic AMP; CRE, cAMP response element; CREB, cAMP response element-binding protein; cPLA2, cytosolic phospholipase A2; DAG, diacylglycerol; DCX, doublecortin; DG, dentate gyrus; DGLA, dihomogammalinolenic acid; DHA, docosahexaenoic acid; EDTA, ethylenediamine tetraacetic acid; EPA, eicosapentaenoic acid; ER, endoplasmic reticulum; FABP, fatty acid binding proteins; GAP-43, growthassociated protein-43; GCL, granular cell layer; GPCR, G protein-coupled receptors; GPR40, G protein-coupled receptor 40; Gaq, G protein a-subunit of the Gq family; Gq, G protein of the Gq family; IGF, insulin-like growth factor; IP3, inositol 1,4,5-trisphosphate; iPLA2, Ca2+-independent phospholipase A2; LT, leukotriene; LTP, long-term potentiation; MAPK, mitogen-activated protein kinase; NFjB, nuclear factor jB; NGF, nerve growth factor; NHR, nuclear hormone receptors; NMDA, N-methyl-D-aspartate; pCREB, phosphorylated cAMP response element-binding protein; PG, prostaglandin; PGI, prostacyclin; PIP2, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PKC, protein kinase C; PPAR, peroxysome proliferator-activated receptors; PS, phosphatidylserine; PLA2, phospholipase A2; PLC, phospholipase C; PPAR, peroxisome proliferator-activated receptors; PSA–NCAM, polysialylated–neural cell adhesion molecule; PUFA, polyunsaturated fatty acids; RXR, retinoid X receptors; SGZ, subgranular zone; SNARE, soluble N-ethylmaleimide-sensitive-factor attachment protein receptor; TrkB, neurotrophin tyrosine kinase receptor type 2; TXA, thromboxane; VEGF, vascular endothelial growth factor. ⇑ Tel.: +81 76 265 2381; fax: +81 76 234 4264. E-mail address: [email protected] 0163-7827/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.plipres.2012.02.001

222

T. Yamashima / Progress in Lipid Research 51 (2012) 221–231

1. Introduction Long chain fatty acids such as docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (ARA, 20:4n-6) are known to modulate membrane fluidity and permeability, and function of membrane-bound proteins [73]. In the mammalian brain, DHA and ARA are the major constitutive fatty acids [93]. Using PET and positron emitting tracers such as [1-11C]ARA and [1-11C]DHA, PUFA incorporation or consumption rates in the human brain were measured to be 17.8 mg/day/1500 g brain for ARA, while 4.6 mg/day/ 1500 g brain for DHA, respectively. An estimated whole brain DHA concentration is 5.13 g with a half-life of 773 days (2.1 years), while a whole brain ARA concentration is 3.78 g with a half-life of 147 days [85]. DHA or ARA is an essential fatty acid mainly anchored in the neuronal membrane, and these two account for approximately 20% of fatty acid content in the brain [28]. DHA is highly enriched in the synaptosomal membrane, synaptic vesicles, and growth cones [68]. DHA in the postsynaptic membranes is crucial for adequate functioning of embedded postsynaptic receptors for neurotransmission [73]. Since humans are poor DHA synthesizers, DHA is essential for the neuronal development in infants, and also required for the maintenance of normal brain function in adults. Accordingly, decreases of DHA in the adult brain are associated with cognitive decline during aging and occurrence of sporadic Alzheimer’s disease. Dietary DHA supplementation in rats increases number of c-Fos-positive neurons and adult neurogenesis in the hippocampus, and improves spatial cognition [105]. In contrast, ARA is abundant in the brain gray matter and its release from membrane phospholipids can serve as an intercellular messenger, which may activate protein kinase C (PKC), and modulate ion channels, transporters and receptors [51,107]. ARA plays a role in generating long-term potentiation (LTP), presumably by stimulating tyrosine kinase and then activating phospholipase Cc (PLCc) [60]. Accordingly, dietary supplementations with ARA and its precursor c-linolenic acid reverse age-dependent impairment of LTP in aged rats [69,56]. Dietary intake of DHA, ARA and eicosapentaenoic acid (EPA, 20:5n-3) may confer benefits in a variety of psychiatric, neurological, and in particular neurodegenerative disorders. The therapeutic effects of PUFA on the brain diseases are currently receiving increasing recognition, making us to ask what would be the underlying mechanism. Despite recent research efforts about PUFA, however, much remains unknown in their pharmacology, mainly because the receptor–ligand interaction has been analyzed insufficiently. G protein-coupled receptors (GPCR) are a family of seventransmembrane-helix, heterotrimeric guanine nucleotide-binding proteins, and contribute to the transmission of extracellular signals to intracellular effectors in response to diverse stimuli such as hormones, neurotransmitters, and environmental stimulants [6,67,89]. Signaling by GPCR is ubiquitous in the brain and retina, and includes many pathways that are related to cognitive function, vision, taste, and odor [91,78]. GPR40 had been one of the orphan (that is, its ligands being unidentified) GPCR that were originally isolated from a human genomic DNA fragment [94]. To identify possible ligands of GPR40, Itoh et al. [47] transfected human GPR40 cDNA in the Chinese hamster ovary cells, added over 1000 chemical compounds, and examined changes in the intracellular Ca2+ concentration ([Ca2+]i) using a fluorometric imaging plate reader system. Diverse PUFA were found to evoke a specific rise of [Ca2+]i in the cells expressing GPR40. Recently, GPR40 was found to be expressed in the progenitor cells in the subgranular zone (SGZ) of normal (non-ischemic) adult monkeys, and suggested to be one of the signals enhancing adult neurogenesis. In addition, GPR40 expression was upregulated in the animals after cerebral ischemia especially in the newborn neurons of the SGZ

[61,62,109]. Furthermore, even in the rat fetal brain neural stem cells devoid of GPR40 gene, ARA or DHA was found to increase [Ca2+]i through activation of GPR40-PLC/IP3 (phospholipase C/inositol trisphosphate) signaling pathway only after the transfection of GPR40 gene [63]. It is suggested from these data that GPR40 should be implicated in adult neurogenesis of primates and may be a key molecule that conducts PUFA signals. cAMP-response-element-binding protein (CREB) is a transcription factor localized within the nucleus, being crucial for the stimulus-transcription coupling. Neurotransmitters and neurotrophins are known to act at the membrane receptors such as neurotrophin tyrosine kinase receptor type 2 (TrkB), a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptors, N-methyl-Daspartate (NMDA) receptors and GPCR. Subsequently, events occurring at the cell surface are transmitted into alterations in gene expression. This can ultimately affect the function of individual neurons and entire neuronal circuits by regulating virtually all types of the protein expression. Drug-induced activation of cAMP signaling promotes proliferation and maturation of newborn neurons [76,37], whereas global inhibition of CREB signaling in immature neurons results in the impaired proliferation and morphological maturity [75,37]. Until now, however, in the newborn neurons of the adult primate brain, nobody could identify the specific neurotrophic factor, neurotransmitter or other molecules that are actually responsible for the phosphorylation of CREB. Using the monkey model of ischemia-enhanced adult neurogenesis, Boneva and Yamashima [11] recently discovered that the cellular localization pattern of phosphorylated CREB (pCREB) is identical to that of GPR40 in the hippocampal neurogenic niche. GPR40 and pCREB were co-expressed in both the mature and newborn neurons in the dentate gyrus (DG), and were similarly upregulated on the second week after ischemia, with their peak being on day 15 after ischemia. It is suggested from these findings that GPR40 and CREB may be functionally linked and could be bi-players working in the same signaling pathway that conducts extracellular PUFA effects. Although dietary PUFA can modulate the synaptic plasticity for the neuronal development and functions in both rodents and primates, it is probable that the molecular and cellular signaling mechanisms induced by PUFA are distinct between the two species. Here, the author reviews novel insights into the ‘PUFA–GPR40– CREB signaling’ that possibly affects cell survival, morphological maturity and synaptic integration of the newborn neurons in the hippocampus of adult primates.

2. PUFA Polyunsaturated fatty acids (PUFA) are subdivided into either n6 (or omega-6, x-6) series that are synthetically derived from linoleic acid (18:2n-6) or n-3 series that are derived from a-linolenic acid (18:3n-3). The lipid numerical symbol, for instance, 18:3n-3 means 18-carbon atoms with 3-double bonds, and a final carbon double bond is located at the third (n-3) from the methyl end (Fig. 1, red circle). Linoleic acid can be converted sequentially via a biosynthetic pathway into other n-6 fatty acids such as c-linolenic acid (18:3n-6), dihomogammalinolenic acid (DGLA: 20:3n-6) and ARA. Similarly, a-linolenic acid is converted into longer chain n-3 fatty acids, but it cannot be efficiently converted to EPA and DHA in humans, and a competition exists between the n-3 and n-6 series for metabolism. Furthermore, the parent essential fatty acids, linoleic acid and a-linolenic acid cannot be synthesized in the human body. Accordingly, linoleic acid, ARA, a-linolenic acid, EPA and DHA must be obtained largely from dietary sources, then they are termed ‘essential fatty acids’.

T. Yamashima / Progress in Lipid Research 51 (2012) 221–231

223

Fig. 1. Overviews of n-6 and n-3 PUFA biosynthetic pathways (left), and mechanism of neuroprotective effects of ARA, EPA and DHA (right). Left: PUFA are subdivided into the n-6 series that are synthetically derived from linoleic acid (18:2n-6), and n-3 series that are derived from a-linolenic acid (18:3n-3). The PUFA biosynthetic pathways proceed through a series of desaturation and elongation steps until 24:5n-6 and 24:6n-3. Subsequently, the chains are shortened by C2 by one cycle of the b-oxidation pathway to form 22:5n-6 and 22:6n-3 (DHA), respectively. But, a-linolenic acid, is not converted very efficiently to EPA (20:5n-3) and DHA (22:6n-3) in humans. Since conversion of n-3 and n-6 PUFA shares the same series of enzymes, a competition exists between the n-3 and n-6 series for metabolism with an excess of one causing a significant decrease in the conversion of another. Right: The neuroprotective effects of EPA and DHA potentially operate through a variety of overlapping mechanisms including direct actions on plasma membranes, altered inflammatory response, and control of gene expression. ARA and EPA, liberated from membrane phospholipids, are precursors of highly-potent but rapidly-degraded ‘local hormones’ collectively called ‘eicosanoids’ that play important roles in inflammatory reactions, vasoconstriction, and platelet aggregation (cited from [33]). Abbreviations: ARA, arachidonic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; cPLA2, cytosolic phospholipase A2; iPLA2, Ca2+-independent phospholipase A2; LT, leukotriene; PG, prostaglandin; PGI, prostacyclin; PPAR, peroxisomal proliferator-activated receptors; PS, phosphatidylserine; RXR, retinoid X receptors; TXA, thromboxane.

Hugh Sinclair first reported that an imbalance in intake between n-3 and n-6 PUFA may cause various diseases including atherosclerosis [100]. Unfortunately, his work remained largely ignored for many years but became widely accepted in 1993, because epidemiological studies on the Greenland Inuit showed that a high relative intake of n-3 PUFA compared to n-6 PUFA is correlated with a decreased prevalence of vascular disease [34]. Major sources of n-6 fatty acids are vegetable oils such as soybean, corn, and safflower, while n-3 fatty acid sources are fish oils such as sardine, mackerel, salmon and tuna. The dietary supply of fatty acids in the former days contained a 1:1 ratio of n-6 to n-3 PUFA. However, the present ratio in the Western countries is larger than 10:1, causing an absolute deficiency of n-3 PUFA. Concomitant with reduced intakes of n-3 PUFA (fish oils), dietary intakes of linoleic acids (vegetable oils) and trans-fatty acids (margarine) as well as saturated fatty acids (meat, butter) are tremendously increasing nowadays. The PUFA biosynthetic pathways (Fig. 1-left) proceed through a progressive series of desaturation and elongation steps, with the n6 and n-3 PUFA series sharing the same enzymes. Syntheses of 24:5n-6 from 18:2n-6 or of 24:6n-3 from 18:3n-3 proceed in the endoplasmic reticulum (ER), and the subsequent b-oxidation to

synthesize 22:5n-6 or 22:6n-3 occurs in the peroxisome. Both 22:5n-6 and 22:6n-3 are translocated back to the ER for the subsequent esterification into the membrane aminophospholipids [102]. Humans show such a gender difference that women have a greater efficiency of conversion [16]. In adult males, for example, conversion of a-linolenic acid to DHA is below 5%, and this further reduces by 50% with n-6 PUFA abundant diets [33]. In contrast, females have more capacity for DHA synthesis preparing for the fetal supply during pregnancy, but show an age-related decrease in D6-desaturase [7]. Accordingly, elderly women over 75 year-old show a significantly decreased phospholipid DHA:EPA ratio, compared to 20–48 year-old younger controls [1]. A supply of preformed DHA and EPA may be the best way to ensure adequate provision for humans, especially in the aged people. One of the major functions of PUFA is to maintain the proper biophysical property and structural integrity of neural membranes. The PUFA effects are to modulate biophysical properties of the cell membrane proteins, receptors and ion channels, as well as to regulate phosphatidylserine (PS) biosynthesis [42]. PUFA are also related to altered inflammatory response (Fig. 1-right): alterations in pro- and anti-inflammatory responses by synthesizing peculiar eicosanoids are mediated through competition between ARA and EPA. Greek word

224

T. Yamashima / Progress in Lipid Research 51 (2012) 221–231

‘eicosa-’ means ‘twenty’, and eicosanoids are short-acting ‘local hormones’ made by oxidation of 20-carbon fatty acids. EPA-derived eicosanoids favor as anti-inflammatory mediators, whereas ARA-derived eicosanoids favor as pro-inflammatory mediators [33]. The eicosanoids of EPA are generally less potent, compared to those of ARA [73]. Non-esterified EPA and DHA being released by phospholipase A2 (PLA2: either cytosolic or Ca2+-independent) from the membrane phospholipids, also produce anti-inflammatory resolvins such as RvE1 and NPD1, respectively [99,46,72]. Growth cones are enriched in PLA2, and this enzyme releases non-esterified PUFA from the membrane phospholipids of growth cones and synaptosomal membranes. Such PUFA mobilization [35] and subsequent activation of soluble N-ethylmaleimide-sensitivefactor attachment protein receptor (SNARE) fusion protein present in growth cones [29], may together provide a neurotrophic effect for the neurite outgrowth that can be induced by PUFA not only during the developmental period but also at the adult and old stages [88]. Membrane expansion at the growth cone requires fusion of newly-synthesized membranes supplied from lipid vesicles with the plasma membrane, and this vesicle fusion is regulated by the SNARE system [87]. Chronic intake of DHA or EPA leads to a significant increase of various synaptic proteins in the hippocampus [17]. Among SNARE fusion proteins, syntaxin 3 is a representative effector molecule involved in the effects especially of n-3 PUFA on the neurite growth. Another effect of n-3 PUFA on synaptic proteins is an increase in the dendritic spine density [90], and this change reflects on an increased plasticity [5]. Apart from their effect mediated via phospholipids and interaction with SNARE fusion proteins, n-3 PUFA have other cellular targets for the neurite outgrowth. For example, they act on two-pore domain potassium channels such as TREK and TRAAK for the extension of growth cones being activated by neuronal stretch [65,2]. Despite abundant evidence of beneficial effects of n-3 PUFA to modulate the neurological function, the mechanisms of their action are still not fully understood.

3. FABP As mentioned above, PUFA are incorporated into the membrane phospholipids as essential components [84], and contribute to the membrane remodeling and neurite growth [88]. These two events were demonstrated to occur simultaneously by both in vitro and in vivo experiments. For example, exposure of cultured cortical neurons to DHA leads to an increase in the membrane contents of PS and phosphatidylethanolamine, and also to an increase in the level of growth-associated protein-43 (GAP-43), a protein associated with growth cone formation [18]. Fat-1 transgenic mice expressing the Caenorhabditis elegans fat-1 gene are capable of producing n-3 PUFA from the n-6 series, and leading to an abundance of n-3 PUFA in their tissues and organs. By using such transgenic fat-1 mice rich in endogenous n-3 PUFA, He et al. [43] showed that increased brain DHA significantly enhances hippocampal neurogenesis and neuritogenesis with an increased density of dendritic spines of CA1 pyramidal neurons in the hippocampus. Compared with the control WT littermates, this fat-1 mice exhibited a better spatial learning performance in the Morris water maze. Concurrently, RT-PCR showed that GAP-43, GluR1, PSD95, synapsin-1, and F-actin were upregulated by 218%, 171%, 249%, 160%, and 140%, respectively, in the hippocampus [43]. Unfortunately, the key elucidation is available only in rodents to explain the PUFA-induced modulation of membrane properties for the related signal transduction and gene expressions. n-3 PUFA can modulate the gene expression in the liver, adipose tissues, and brain [82,21,54]. The altered genes in the rat brain in response to dietary n-3 PUFA control synaptic plasticity, cytoskeleton and membrane association, signal transduction, ion channel

formation, energy metabolism, and regulatory proteins. Interestingly, several genes (calmodulins, etc.) participating in the signal transduction processes were overexpressed in response to n-3 PUFA [54]. Clarke and Jump [20] proposed that n-3 PUFA are transferred to the nucleus, modify certain nuclear proteins, and finally regulate DNA–protein interactions. Non-esterified EPA and DHA regulate gene expression via nuclear hormone receptors (NHR) such as retinoid X receptors (RXR) [25,26] and peroxisome proliferator-activated receptors (PPAR) [31,32]. As DHA is a ligand for RXR in the nucleus [31], direct DHA–RXR signalings are closely related to brain development, synaptic plasticity, neuronal protection, and reverse of age-related changes in rodents [103]. For the activation of RXR or PPAR, however, a cargo protein is indispensable for the water-insoluble PUFA to be transported from the cell surface to the nuclei in neurons. Then, direct gene regulation by PUFA is dependent whether the neurons express such cargo protein in the cytoplasm. Although PUFA are essentially hydrophobic, binding with albumin and/or lipocalins highly increases their aqueous solubility, facilitating circulation within the blood stream. Fatty acid binding proteins (FABP) transport PUFA to appropriate intracellular compartments to let them exert their functions (Fig. 2, upper left schema) [23]. FABP are important, (1) as sources of energy stored in triacylglycerol and produced in muscles and liver, (2) for formation of complex lipids such as phospholipids and cholesterol, or (3) for synthesizing hormones and signaling compounds. For example, in liver cells, PUFA, being transported to the nuclei by FABP1, downregulate expression of genes of lipid synthesis, but simultaneously upregulate genes of fatty acid oxidation [22]. Among various FABP, FABP 3, 5 and 7 are abundant in the brain. FABP3 (heart-type) shows affinity to n-6 PUFA such as ARA; FABP5 (epidermal-type) to saturated fatty acids, and FABP7 (brain-type) to n-3 PUFA such as DHA [41]. Furthermore, FABP5 can also bind PUFA such as ARA, DHA, and EPA [58]. For example, in the rodent brain FABP3 is present in the postnatal neurons, FABP5 in astrocytes, glial cells, radial glia, and neurons, while FABP7 in astrocytes and radial glia [80]. Intriguingly, FABP 3 and 5 are expressed in neurons of the rodent [80], but in the monkey brain FABP 3 and 7 were expressed in the cerebellar Purkinje cells, but not in the hippocampal neurons [8–10] (Fig. 2A and E). Accordingly, in the rodent hippocampus PUFA can directly access to the neuronal nuclei with the aid of FABP 3 and/or 5, but PUFA cannot access to the nuclei in the primate hippocampal neurons which are actually devoid of FABP. DHA–RXR or DHA–PPAR signalings can occur, if DHA is transported to the nuclei with the aid of FABP7 (or FABP5); in primates this is possible in the Bergmann glia (Fig. 2B) or the SGZ astrocytes (Fig. 2C) and progenitors (Fig. 2D) expressing FABP7 (or FABP5), but impossible in the newborn neurons devoid of FABP7 or FABP5 (Fig. 2E) [9]. Then, an alternative signaling pathway that can respond to the cell surface PUFA is indispensable to influence the gene transcription for survival, differentiation and integration of newborn neurons, but such PUFA-mediated signaling had been unknown until recently especially in primates. One exception of this is a-synuclein, a synaptic modulatory protein implicated in the pathogenesis of Parkinson disease, that can interact and sequester ARA to modulate SNARE-mediated exocytosis at the synaptic transmission in humans [30]. In contrast to our understanding of the necessity of PUFA for the brain, their role as a signal messenger is poorly understood.

4. GPR40 Until 2003, G protein-coupled receptor 40 (GPR40) was a member of so-called ‘orphan (its ligands unidentified)’ GPCR that were originally isolated from a human genomic DNA fragment [94].

T. Yamashima / Progress in Lipid Research 51 (2012) 221–231

225

Fig. 2. Putative functions of FABP in the cell, and immunophenotypes of FABP7-positive cells in the monkey brain. Left upper schema: Fatty acid accompanied by FABPs in the cell is trafficking to various organelles, for example, to the nucleus for the control of lipid-mediated transcriptional programs via NHR such as PPAR and RXR (cited from [38]). NHR, nuclear hormone receptors. In the normal (non-ischemic) monkey cerebellum (A and B), parvalbumin-positive Purkinje cells are positive for FABP-7 (A) whereas S100bpositive Bergmann glia are negative (B, arrow) (cited from [8]). ML, molecular layer; PCL, Purkinje cell layer; GCL, granular cell layer. In the postischemic day 15 SGZ (C–E), FABP-7 shows coexpression with S-100b-positive astoglia (C, rectangle) and nestin-positive progenitors (D, rectangle), but not with bIII-tubulin-positive immature neurons (E), although using the same antibody and staining procedure (cited from [9]). GCL, granular cell layer; SGZ, subgranular zone. Bar = 50 lm (A and B), 10 lm (C–E).

However, fatty acids had already been identified as natural ligands for the nuclear receptors such as PPAR [40,79,4] and RXR [31]. Furthermore, GPCR specific for fatty acid derivatives such as prostaglandins or leukotrienes had been identified [24,92]. These two observations indicated that fatty acids should have a specific cell surface receptor for themselves. Based on such an idea, Briscoe et al. [15], Itoh et al. [47], and Kotarsky et al. [57], independently identified the cell surface receptor which can be activated by fatty acids at concentrations corresponding to their physiological plasma levels. These three groups demonstrated that medium and long chain saturated and unsaturated fatty acids can activate GPR40 in a dose-dependent manner. Of all the fatty acids screened by a ligand fishing strategy in HEK293 cells expressing human GPR40, potency did not correlate with carbon chain length or degree of saturation across the unsaturated fatty acids. The rank order of potency of fatty acids for GPR40 in HEK293 cells was not equivalent to the well-known relative efficacy of fatty acids for the brain. DHA showed a pEC50 (the negative logarithm of EC50: the concentration that produces 50% of the maximal response) of 5.37, while ARA showed a pEC50 of 4.92 [15]. Another study reported that DHA showed the most potent GPR40 agonist activity (EC50 = 1.1 lM; pEC50 6.6), whereas the methyl ester of linoleic acid showed no activity (EC50 > 300 lM) [47]. Given the large number of fatty acids that can become agonists for GPR40, it is conceivable that the physiologically relevant fatty acid for GPR40 may vary in a tissue-dependent fashion. Lack of specificity of GPR40 for a single fatty acid implies that its selectivity might be determined by the local tissue-specific environment. Inductions of [Ca2+]i in HEK293 cells were exactly dependent on the presence of GPR40, as any fatty acids could not elicit a response

in the cells not expressing GPR40 [15]. Similarly, using rat pheochromocytoma PC12 cells (a neuronal cell model) with GPR40 gene transfection, the dynamic change of [Ca2+]i was shown to occur in response to 10 lM ARA. Even after Ca2+ was removed from the solution with ethylenediamine tetraacetic acid (EDTA), ARA-induced intracellular Ca2+ mobilization was observed. On the contrary, the inositol 1,4,5-trisphosphate (IP3) receptor-specific antagonist, xestospongin C blocked ARA-induced Ca2+ increase under the Ca2+-free condition [109]. ARA application after mockinfection of GPR40 did not elicit an increase of [Ca2+]i. These data altogether suggested that the intracellular Ca2+ stores are the main source of the ARA-induced and GPR40-mediated Ca2+ mobilization. GPR40 was scarcely detected in the rat brain [47] and not expressed in the rat neural stem cells [63]. Accordingly, in the wild-type rat neural stem cells, no change of [Ca2+]i was observed in response to DHA even at the 15 lM concentration. On the contrary, in the rat neural stem cells transfected with the GPR40 gene, [Ca2+]i rapidly increased and this was maintained for a few minutes [63]. Such DHA-induced Ca2+ mobilization also occurred independent of extracellular Ca2+, but dependent on IP3. Furthermore, in the cultured rat neural stem cells transfected with the GPR40 gene, Ma et al. [63] demonstrated that DHA-induced neuronal differentiation, neurite growth and branching of adult rat stem cells, were mediated in part through GPR40. Levels of free fatty acids in the plasma are usually 0.2–1.7 mM but more than 99% are tightly bound with serum albumin, so that the concentration of free (unbound) fatty acids is approximately 0.01–10 lM [101]. Accordingly, both ARA of 10 lM concentration and DHA of 15 lM concentration are sufficient to provoke Ca2+ mobilization in the living brain.

226

T. Yamashima / Progress in Lipid Research 51 (2012) 221–231

Fig. 3. Postischemic upregulation of GPR40 and pCREB being associated with enhanced hippocampal neurogenesis. On Western blots, both GPR40 (A) and pCREB (B) are upregulated significantly after transient global brain ischemia, becoming maximal on day 15 (cited from [62,11]). (C) Non-ischemic control; d15, day 15 after the ischemic insult; Pancreas, positive control of GPR40. Immunohistochemical localization of phosphorylated CREB (pCREB, green) is almost identical with that of GPR40 (red). Compared to the control (Cont), GPR40/pCREB double-positive cells show a significant increase (arrows) on day 9 (d9) (unpublished data). GCL, granular cell layer; SGZ, subgranular zone. Bar = 50 lm (C and D).

Although GPR40 is abundantly expressed in the brain of humans and monkeys [15,61], its role in the brain have been unclarified. However, the author’s group recently proposed implications of GPR40 in the adult neurogenesis of monkeys [62,109]. In the hippocampal neurogenic niche of normal (non-ischemic) adult monkeys, GPR40 was found in progenitor cells (both neural and neuronal), mature neurons as well as in astrocytes residing in the subgranular zone (SGZ) [61]. Moreover, compared to the nonischemic control, monkeys with ischemia-enhanced adult neurogenesis showed a remarkable upregulation of GPR40 on Western blotting (Fig. 3A). GPR40 immunolocalization pattern after ischemia (Fig. 3D) was essentially similar to the control (Fig. 3C) [62], but the newborn neurons of the SGZ showed a predominant expression (Fig. 3D, arrows). These findings suggest that GPR40 should be a key molecule that conducts PUFA signals in the adult neurogenic niche of primates. GPR40 couples with a G protein asubunit of the Gq family (Gaq). Because signaling pathways downstream of Gaq-coupled GPCR presumably include activation of mitogen-activated protein kinase (MAPK) and subsequent stimulation of transcriptional activity, it is plausible that activation of GPR40 can regulate a transcription factor. It is likely that in the rodent neurogenic niche FABP transport extracellular PUFA to the nucleus of the newborn neurons because of the lack of GPR40, whereas in the primate neurogenesis niche, PUFA being transported to the surface of the newborn neurons, bind with the cell surface GPR40 receptor to induce intracellular signaling because of their lack of FABP [9]. 5. CREB Adult neurogenesis may allow the brain to respond to environmental demands such as increased intellectual stimuli, exercise, and brain injury. Both neuronal activity and neurotrophic factors have been thought to be a major modulator, yet little is known about the corresponding signaling pathway for adult neurogenesis. CREB belongs to the family of leucine zipper transcription factors that are expressed in a variety of tissues. It functions as an effector molecule that brings about cellular changes in response to extracellular stimuli. Among various gene regulatory factors, CREB is

implicated in the complex and diverse processes of neurons ranging from development to plasticity. CREB regulates cell proliferation, differentiation, and survival in the developing brain, and mediates such responses as neuronal plasticity, learning, and memory in the adult brain [59]. Phosphorylation of a serine residue (S133) in its kinase-inducible domain is critical to translate effects of extracellular stimuli into the related-gene alterations. CREB phosphorylation can be achieved by a number of upstream signaling cascades such as cyclic AMP (cAMP)–protein kinase A (PKA) cascade, the MAPK signaling pathway, as well as calmodulin-dependent kinases II and IV (CaMKII/IV) and phospholipase C (PLC)–PKC signaling cascades [50,74]. At present, however, there is no consensus concerning the exact upstream regulator of CREB-signaling in adult-born neurons. Modulation of CREB-signaling may occur at multiple levels; the binding of neurotransmitters (e.g. GABA, glutamate, serotonin), neurotrophins (BDNF), or growth factors (VEGF, IGF) with the membrane-bound receptors triggers distinct intracellular signaling cascades, all of which result in the CREB phosphorylation [104,70]. Among various signaling pathways for the CREB phosphorylation, the pathway triggered by GPCR stimulation of adenylyl cyclase (AC) has been characterized most thoroughly. For example, stimulation of dopamine D1-like receptors activates excitatory GS-coupled receptors, which stimulates AC and accumulates cAMP to cause liberation of the catalytic subunits of cAMP-dependent PKA [19]. Here, it is intriguing to note that GPR40, being expressed in the hippocampal neurogenic niche of adult monkeys (Fig. 3C and D), is one of the GPCR that are capable of activating CREB-signaling. As CREB is required for the neurotrophic factor-dependent survival of cultured neurons [14,86], the possibility that phosphorylated CREB (pCREB) influences also cell survival in vivo is fascinating. Systemic activation of cAMP signaling promotes proliferation and morphological maturation of newborn cells [76,37], whereas global inhibition of CREB signaling results in the impaired proliferation and maturation of immature neurons in mice [75,37]. Immunohistochemical studies using anti-pCREB antibody showed that pCREB is present in the vast majority of newly generated immature neurons of the SGZ of mice (Fig. 4A) [75,76]. Furthermore, both the pharmacological and genetic studies provided

T. Yamashima / Progress in Lipid Research 51 (2012) 221–231

227

Fig. 4. Distribution, dynamic changes, and expression of phosphorylated CREB (phospho-CREB or pCREB) during hippocampal neurogenesis of adult mice. The phosphorylated CREB (A) is localized at the newborn neurons in the SGZ, but not at the mature granular cells (cited from [76]). Expression of pCREB and other markers corresponding to different stages of adult neurogenesis (B). Phosphorylation of CREB is preceded by NeuroD expression, while loss of CREB phosphorylation is followed by calbindin expression (cited from [48]). CREB phosphorylation during maturation of adult-born neurons (C). The stable pCREB expression overlaps with the expression of doublecortin (DCX). NeuN- or calbindin-positive mature neurons show only transient pCREB expression in mice (cited from [70]).

important insights into the role of CREB in the regulation of adult neurogenesis [76,37]. The pCREB is initially observed in the newborn neurons 5–7 days after birth, and the vast majority of immature neurons show CREB phosphorylation for the subsequent 2– 3 weeks (Fig. 4B) [48]. pCREB immunoreactivity can be observed almost during the expression of an immature neuronal marker, doublecortin (DCX) and is gradually downregulated when newborn neurons initiate the expression of mature neuronal marker NeuN or calbindin, instead of DCX (Fig. 4B and C) [48,70]. n-3 PUFA deprivation for 15 weeks decreased DHA concentration in the rat frontal cortex, and concomitantly reduced p38 MAPK activity, CREB phosphorylation and DNA binding activity, and expression of brain-derived neurotrophic factor (BDNF) protein and mRNA [83]. In the rat neurons, DHA can transfer within the cell with the aid of FABP, and directly activate p38 MAPK, CREB and BDNF. On the contrary, in the primate neurons devoid of such intercellular cargo protein, the same can hardly occur. Instead, CREB phosphorylation with the resultant BDNF synthesis can be induced by the binding of extracellular PUFA with the cell surface receptor, GPR40. Because GPR40 is not expressed in the rodent brain, paucity of the rodent experimental paradigms disturbs to prove a causal relationship among PUFA–GPR40–CREB signaling, However, PUFA such as DHA and ARA play a crucial role for the GPR40-mediated, internal Ca2+ mobilization by the IP3-dependent manner as described in the previous chapter. Accordingly, GPR40 is assumed to be a strong candidate that can conduct the signal of extracellular PUFA to CREB in the primate neurons, if considering GPR40 expression is most abundant in the brain among multiple human tissues [15,47]. Using a monkey model of ischemia-enhanced hippocampal neurogenesis, Boneva and Yamashima [11] recently found that expression of pCREB was upregulated significantly on days 5–15 after transient global brain ischemia (Fig. 3B), and this occurred not only in bromodeoxyuridine (BrdU)-positive progenitor cells

and newborn neurons but also in mature granular cells. In the adult monkey hippocampus, the expression pattern of pCREB was almost identical with that of GPR40 in both the normal (non-ischemic) and post-ischemic states (Fig. 3C and D) [11]. Compared to the control (Fig. 3C), GPR40/pCREB double-positive cells showed a significant increase on day 9 (Fig. 3D). Western blotting data (Fig. 3A and B) were compatible with the immunohistochemistry data (Fig. 3C and D), both of which indicated a functional link between GPR40 and pCREB. Interestingly, the immunolocalization of CREB was the same between rodents and monkeys, but that of pCREB was distinct. In mice [76], pCREB was localized only in the polysialylated–neural cell adhesion molecule (PSA–NCAM)-positive immature neurons at the hilar side of the granule cell layer (Fig. 4A) as seen in the postnatal rats [3]. On the contrary, in monkeys it was localized not only in PSA–NCAM-positive newborn neurons but also in the mature granular cells (Fig. 5A1, A2, B, and C). In addition, BDNF was expressed in some, but not all, of the PSA–NCAM-positive newborn neurons in the non-ischemic controls (Fig. 5D1). Although the number of the BDNF/PSA–NCAM double-positive newborn neurons increased on day 15 after ischemia (Fig. 5D2), BDNF immunoreactivity of newborn neurons was observed not in the perinuclear cytoplasm but in the dendrites (Fig. 5D3 arrow) [11]. This showed a remarkable contrast with the mature granular cells showing BDNF immunoreactivity in the perinuclear cytoplasm (Fig. 5D1, D2, and D3). Furthermore, the PSA–NCAM-positive newborn neurons did not express a pCREBregulated gene product, TrkB [59] that is a receptor for BDNF [11]. It is suggested from these data that in PSA–NCAM- or DCXpositive adult-born neurons of monkeys (Fig. 5B and C), BDNF is at downstream of enhanced CREB function. In summary, the evidence for a link between GPR40 and CREB signaling is distinct, but still insufficient. Additional evidence focusing on the primate brain is indispensable to prove the PUFA–GPR40–CREB signaling pathway (Fig. 6); for example, it

228

T. Yamashima / Progress in Lipid Research 51 (2012) 221–231

Fig. 5. Expression of pCREB and BDNF in both the newborn and mature neurons of adult monkeys. pCREB is expressed not only in polysialylated–neural cell adhesion molecule (PSA–NCAM)-, doublecortin (DCX)-, or brain-derived neurotrophic factor (BDNF)-positive newborn neurons in the SGZ, but also in the mature granular cells (note difference from Fig. 4A). In both the control (A1) and the postischemic day 15 dentate gyrus after ischemia (A2), double staining for pCREB and PSA–NCAM can be seen. High magnification of pCREB/PSA–NCAM (B) and pCREB/DCX (C) double-positive cells on the postischemic day 15, shows the expression of pCREB in the newborn and/or immature neurons. Compared to the non-ischemic control (D1), expression of BDNF is upregulated on the postischemic day 15 (D2), and BDNF immunoreactivity in the newborn neuron is seen in the dendrite (arrow) but not in the perinuclear cytoplasm (rectangle in D2 is enlarged in D3) (cited from [11]). GCL, granular cell layer; SGZ, subgranular zone. Bar = 50 lm (A1 and A2), 20 lm (B, C, D1, and D2).

Fig. 6. Schematic chart of the possible ‘PUFA–GPR40–CREB signaling pathway’ in the adult neurogenic niche of primates. FABP transport PUFA from the blood vessels to different intracellular organelles of the SGZ astrocytes (See Fig. 2C) for b-oxidation, membrane synthesis, enzyme activity modulation, and regulation of gene transcription through PPAR. Concurrently, FABP may convey PUFA through the astrocyte cytoplasm and release them as paracrine signals to the newborn neurons in the neurogenic niche. PUFA, as a signaling ligand, bind with the cell surface receptor GPR40 and trigger an intracellular cascade, which leads to CREB phosphorylation and gene transcription of BDNF, PSA–NCAM, etc. in the newborn neurons (cited from [10]). Abbreviations: PUFA, polyunsaturated fatty acids; FABP, fatty acid binding proteins; PPAR, peroxisome proliferator-activated receptors; GPR40, G protein-coupled receptor 40; Gq, G protein of the Gq family; PLC, phospholipase C; PIP2, phosphoinositol diphosphate; IP3, inositol trisphosphate; DAG, diacylglycerol; PKC, protein kinase C; ER, endoplasmic reticulum; pCREB, phosphorylated cAMP response element-binding protein; BDNF, brain-derived neurotrophic factor; PSA–NCAM, polysialylated–neural cell adhesion molecule.

would be beneficial to examine the dynamic change of PSA–NCAM/ GPR40/pCREB triple-positive cell number after the dietary modulation of PUFA levels, using a large number of non-human primates before and after cerebral ischemia.

6. BDNF and PSA–NCAM Because the majority (60–65%) of BrdU- and pCREB-positive cells in the SGZ are also positive for PSA–NCAM when analyzed

1–3 weeks after BrdU administration, Nakagawa et al. [76] suggested that the cAMP–CREB pathway regulates synthesis of PSA– NCAM. Because polysialic acid (PSA) serves as a potent negative regulator of NCAM-mediated cell adhesion via its unusual biophysical properties [13], the newborn neurons can extend their neurites to the final destination for building new synaptic contacts by skipping unnecessary ones. Furthermore, CREB signaling is known to play a crucial role for regulating survival and maturation of newborn hippocampal neurons [48]. For this purpose, another important target protein of phosphorylated CREB is BDNF which may

T. Yamashima / Progress in Lipid Research 51 (2012) 221–231

modify synaptic plasticity, structural remodeling, and finally behavioral effects. These data, combined together, suggest that the activated CREB mainly regulates synthesis of BDNF and PSA– NCAM in the hippocampal neurogenic niche, because at least these two are indispensable for the maturation and migration of newborn neurons. Adult hippocampal neurogenesis and neuroplasticity are positively affected by neurotrophic factors such as BDNF, nerve growth factor (NGF), and neurotrophin-3. Among these, BDNF has been intensively studied and shown to be involved in learning and memory, and synaptic plasticity [81]. It is the most abundant and widely expressed neurotrophin in the mammalian nervous system. Exercise-induced structural and functional changes have been documented in various brain regions especially in the hippocampus through regulation of BDNF. Hippocampal LTP is impaired in mice lacking BDNF in their neurons, whereas BDNF enhances LTP in the hippocampus [55,36]. Environmental enrichment and antidepressants can induce both hippocampal neurogenesis and BDNF expression [77,52,53,106,64,66]. On Western blotting, upregulation of GPR40 and pCREB in the monkey hippocampus was remarkable on the second week after the ischemic insult (Fig. 3A and B), which showed a marked contrast compared to BDNF showing no significant change [11]. This is presumably because the mature granular cells, a major population of the DG, are consistently synthesizing BDNF both before ischemia and after ischemia (Fig. 5D1, D2 and D3). Accordingly, increment of BDNF in the newborn neurons became less prominent in the homogenized tissue, as the number of newborn neurons was much less compared to the huge number of mature granular cells. In contrast, after ischemia, newborn neurons in the SGZ, although a minor population in the DG, must synthesize abundant PSA–NCAM (Fig. 5A1, A2, and B). Accordingly, for the PSA–NCAM synthesis, upregulation of GPR40 and pCREB became significant as revealed by Western blotting (Fig. 3A and B) and immunohistochemistry (Fig. 3C and D). It is suggested from these data that acute and intense activation of GPR40 and CREB may be occurring in the newborn neurons of the SGZ, while sustained and mild activation may be occurring in the pre-existing mature neurons. This can presumably produce differential effects on neurite extension, branching and spine morphology between the newborn neurons and pre-existing mature neurons. pCREB may be also involved in the expression of also PSA synthases such as STX and/or ST8SiaIV, responsible for the synthesis of PSA–NCAM. Both STX and ST8SiaIV are expressed in the granular cell layer of hippocampus, although at much lower levels in adults compared to during development [45]. PSA–NCAM is abundantly expressed during development and disappears after birth or in the early postnatal development. However, PSA–NCAM is again expressed in the granular cells of the DG that undergo synaptic plasticity or remodeling [96,97,98,12]. PSA–NCAM-positive newborn neurons differ from mature neurons in their passive (input resistance) and active membrane properties (such as calcium spikes that boost fast sodium action potentials) as well as in their enhanced ability to develop LTP [95]. The link between pCREB and PSA–NCAM was first suggested in rodents [3,76], and confirmed in monkeys [11]. Since PSA–NCAM-positive newborn neurons express pCREB in the nuclei (Fig. 5A1, A2, and B), and the number of pCREB/PSA–NCAM double-positive newborn neurons increase significantly on days 5, 9 and 15 after ischemia [11], it is conceivable that CREB triggered also transcription of a PSA synthase enzyme gene which is responsible for the PSA–NCAM synthesis [76]. In many cellular contexts CREB is transiently activated by its phosphorylation lasting only 30–60 min [108,49], but CREB phosphorylation is persistent in the newborn neurons as long as 2–3 weeks in rodents (Fig. 4B) [75,39,48,44] and at least for 10 days in monkeys (Fig. 3) [11]. As neurons are capable of

229

distinguishing between acute and gradual changes in the receptor activation, it is likely that not only the identity of the upstream signal but also its strength and timing control the activation of CREB-signaling and the subsequent transcription. Anyway, differential phosphorylation patterns in response to diverse upstream signals might provide an interesting mechanism for the integration of multiple signals through CREB. Differential formation of CREB dimers and targeting of CREB to distinct cAMP response element (CRE) sites also might provide another mechanism to elicit differential transcriptional activity and output [70]. The binding properties of the CREB dimer with the consensus or variant CRE sites varies depending on the intracellular Mg2+ concentration [27,71]. Furthermore, interaction of CREB with a number of co-factors enables CREB-signaling to regulate distinct sets of target genes [70]. A detailed study is needed to clarify the mechanisms involved in the regulation of CREB-dependent transcription and CREBdependent development of neurons in the adult neurogenic niches. 7. Concluding remarks Adult hippocampal neurogenesis possibly contributes to learning, memory and mood, but its underlying mechanism still remains elusive. The effect of PUFA on adult neurogenesis is essentially the same between rodents and primates, but their signaling pathway should be distinct because the primate neurons lack a cargo protein but have the cell surface PUFA receptor. Instead of FABP facilitating interaction of PUFA with nuclear transcription factors in rodents, GPR40 conducts extracellular PUFA signals to the nucleus for phosphorylating CREB in primates. It appears that the primate neurons are associated with a specific ‘PUFA–GPR40–CREB signaling’ pathway (Fig. 6) that potentially influences adult-born neurons via syntheses of not only BDNF but also PSA–NCAM. Characterization of the ‘PUFA–GPR40–CREB signaling’ pathway may add new insights into adult neurogenesis specific for primates. Acknowledgments This work was supported by a Grant (Kiban-Kennkyu (B):18390392, 22390273) from the Japanese Ministry of Education, Culture, Sports, Science and Technology. References [1] Babin F, Abderrazik M, Favier F, Cristol JP, Léger CL, Papoz L, et al. Differences between polyunsaturated fatty acid status of non-institutionalised elderly women and younger controls: a bioconversion defect can be suspected. Eur J Clin Nutr 1999;53:591–6. [2] Bang H, Kim Y, Kim D. TREK-2, a new member of the mechanosensitive tandem-pore K+ channel family. J Biol Chem 2000;275:17412–9. [3] Bender RA, Lauterborn JC, Gall CM, Cariaga W, Baram TZ. Enhanced CREB phosphorylation in immature dentate gyrus granule cells precedes neurotrophin expression and indicates a specific role of CREB in granule cell differentiation. Eur J Neurosci 2001;13:679–86. [4] Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med 2002;53:409–35. [5] Blanpied TA, Ehlers MD. Microanatomy of dendritic spines: emerging principles of synaptic pathology in psychiatric and neurological disease. Biol Psychiatry 2004;55:1121–7. [6] Bockaert J, Pin JP. Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J 1999;18:1723–9. [7] Bolton-Smith C, Woodward M, Tavendale R. Evidence for age-related differences in the fatty acid composition of human adipose tissue, independent of diet. Eur J Clin Nutr 1997;51:619–24. [8] Boneva NB, Mori Y, Kaplamadzhiev DB, Kikuchi H, Zhu H, Kikuchi M, et al. Differential expression of FABP 3, 5, 7 in infantile and adult monkey cerebellum. Neurosci Res 2010;68:94–102. [9] Boneva NB, Kaplamadzhiev DB, Sahara S, Kikuchi H, Pyko IV, Kikuchi M, et al. Expression of fatty acid-binding proteins in adult hippocampal neurogenic niche of postischemic monkeys. Hippocampus 2011;21:162–71. [10] Boneva NB, Kikuchi M, Minabe Y, Yamashima T. Neuroprotective and ameliorative actions of polyunsaturated fatty acids against neuronal diseases: implication of fatty acid-binding proteins (FABP) and G protein-

230

[11] [12]

[13] [14]

[15]

[16] [17]

[18]

[19] [20] [21]

[22]

[23] [24]

[25]

[26]

[27]

[28]

[29] [30]

[31]

[32] [33] [34]

[35] [36]

[37]

[38] [39]

[40]

[41]

T. Yamashima / Progress in Lipid Research 51 (2012) 221–231 coupled receptor 40 (GPR40) in adult neurogenesis. J Pharmacol Sci 2011;116:163–72. Boneva NB, Yamashima T. New insights into ‘GPR40–CREB interaction in adult neurogenesis’ specific for primates. Hippocampus 2012;22:896–905. Bonfanti L, Olive S, Poulain DA, Theodosis DT. Mapping of the distribution of polysialylated neural cell adhesion molecule throughout the central nervous system of the adult rat: an immunohistochemical study. Neuroscience 1992;49:419–36. Bonfanti L. PSA–NCAM in mammalian structural plasticity and neurogenesis. Prog Neurobiol 2006;80:129–64. Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME. Cell survival promoted by the Ras–MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 1999;286:1358–62. Briscoe CP, Tadayyon M, Andrews JL, et al. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem 2003;278:11303–11. Burdge GC. Metabolism of a-linolenic acid in humans. Prostaglandins Leukot Essent Fatty Acids 2006;75:161–8. Cansev M, Wurtman RJ. Chronic administration of docosahexaenoic acid or eicosapentaenoic acid, but not arachidonic acid, alone or in combination with uridine, increases brain phosphatide and synaptic protein levels in gerbils. Neuroscience 2007;148:421–31. Cao D, Xue R, Liu Z. Effects of docosahexaenoic acid on the survival and neurite outgrowth of rat cortical neurons in primary cultures. J Nutr Biochem 2005;16:538–46. Carlezon Jr WA, Duman RS, Nestler EJ. The many faces of CREB. Trends Neurosci 2005;28:436–45. Clarke SD, Jump DB. Dietary polyunsaturated fatty acid regulation of gene transcription. Annu Rev Nutr 1994;14:83–98. Clarke SD. Polyunsaturated fatty acid regulation of gene transcription: a molecular mechanism to improve the metabolic syndrome. J Nutr 2001;131:1129–32. Clarke SD. The multi-dimensional regulation of gene expression by fatty acids: polyunsaturated fats as nutrient sensors. Curr Opin Lipidol 2004;15:13–8. Coe NR, Bernlohr DA. Physiological properties and functions of intracellular fatty acid-binding proteins. Biochim Biophys Acta 1998;1391:287–306. Coleman RA, Smith WL, Narumiya S. International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev 1994;46:205–29. Corcoran J, Shroot B, Pizzey J, Maden M. The role of retinoic acid receptors in neurite outgrowth from different populations of embryonic mouse dorsal root ganglia. J Cell Sci 2000;113:2567–74. Corcoran J, So PL, Barber RD, Vincent KJ, Mazarakis ND, Mitrophanous KA, et al. Retinoic acid receptor b2 and neurite outgrowth in the adult mouse spinal cord in vitro. J Cell Sci 2002;115:3779–886. Craig JC, Schumacher MA, Mansoor SE, Farrens DL, Brennan RG, Goodman RH. Consensus and variant cAMP-regulated enhancers have distinct CREBbinding properties. J Biol Chem 2001;276:11719–28. Crawford MA, Sinclair AJ. Nutritional influences in the evolution of mammalian brain: lipids, malnutrition and the developing brain. In: Ciba Foundation symposium; 1971. p. 267–92. Darios F, Davletov B. Omega-3 and omega-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3. Nature 2006;440:813–7. Darios F, Ruipérez V, López I, Villanueva J, Gutierrez LM, Davletov B. aSynuclein sequesters arachidonic acid to modulate SNARE-mediated exocytosis. EMBO Rep 2010;11:528–33. de Urquiza AM, Liu S, Sjöberg M, Zetterström RH, Griffiths W, Sjövall J, et al. Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science 2000;290:2140–4. Duplus E, Forest C. Is there a single mechanism for fatty acid regulation of gene transcription? Biochem Pharmacol 2002;64:893–901. Dyall SC, Michael-Titus AT. Neurological benefits of omega-3 fatty acids. Neuromol Med 2008;10:219–35. Dyerberg J. Epidemiology of n-3 fatty acids and disease. In: De Caterina R, Endres S, Kristensen SD, Schmidt EB, editors. n-3 Fatty acids and vascular disease. London: Springer-Verlag; 1993. p. 3–10. Farooqui AA, Horrocks LA. Brain phospholipases A2: a perspective on the history. Prostaglandins Leukot Essent Fatty Acids 2004;71:161–9. Figurov A, Pozzo-Miller LD, Olafsson P, Wang T, Lu B. Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 1996;381:706–9. Fujioka T, Fujioka A, Duman RS. Activation of cAMP signaling facilitates the morphological maturation of newborn neurons in adult hippocampus. J Neurosci 2004;24:319–28. Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 2008;7:489–503. Giachino C, De Marchis S, Giampietro C, Parlato R, Perroteau I, Schütz G, et al. cAMP response element-binding protein regulates differentiation and survival of newborn neurons in the olfactory bulb. J Neurosci 2005;25:10105–18. Göttlicher M, Widmark E, Li Q, Gustafsson JA. Fatty acids activate a chimera of the clofibric acid activated receptor and the glucocorticoid receptor. Proc Natl Acad Sci USA 1992;89:4653–7. Hanhoff T, Lücke C, Spener F. Insights into binding of fatty acids by fatty acidbinding proteins. Mol Cell Biochem 2002;239:45–54.

[42] Hamilton L, Greiner R, Salem Jr N, Kim HY. n-3 Fatty acid deficiency decreases phosphatidylserine accumulation selectively in neuronal tissues. Lipids 2000;35:863–9. [43] He C, Qu X, Cui L, Wang J, Kang JX. Improved spatial learning performance of fat-1 mice is associated with enhanced neurogenesis and neuritogenesis by docosahexaenoic acid. Proc Natl Acad Sci USA 2009;106:11370–5. [44] Herold S, Jagasia R, Merz K, Wassmer K, Lie DC. CREB signalling regulates early survival, neuronal gene expression and morphological development in adult subventricular zone neurogenesis. Mol Cell Neurosci 2011;46:79–88. [45] Hildebrandt H, Becker C, Glüer S, Rösner H, Gerardy-Schahn R, Rahmann H. Polysialic acid on the neural cell adhesion molecule correlates with expression of polysialyltransferases and promotes neuroblastoma cell growth. Cancer Res 1998;58:779–84. [46] Hong S, Gronert K, Devchand PR, Moussignac RL, Serhan CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. J Biol Chem 2003;278:14677–87. [47] Itoh Y, Kawamata Y, Harada M, et al. Free fatty acids regulate insulin secretion from pancreatic b cells through GPR40. Nature 2003;422:173–6. [48] Jagasia R, Steib K, Englberger E, Herold S, Faus-Kessler T, Saxe M, et al. GABA– cAMP response element-binding protein signaling regulates maturation and survival of newly generated neurons in the adult hippocampus. J Neurosci 2009;29:7966–77. [49] Ji Y, Lu Y, Yang F, Shen W, Tang TT, Feng L, et al. Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons. Nat Neurosci 2010;13:302–9. [50] Johannessen M, Delghandi MP, Moens U. What turns CREB on? Cell Signal 2004;16:1211–27. [51] Kawasaki A, Han MH, Wei JY, Hirata K, Otori Y, Barnstable CJ. Protective effects of arachidonic acid on glutamate neurotoxicity in rat retinal ganglion cells. Invest Opthalmol Vis Sci 2002;43:1835–42. [52] Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature 1997;386:493–5. [53] Kempermann G, Kuhn HG, Gage FH. Experience-induced neurogenesis in the senescent dentate gyrus. J Neurosci 1998;18:3206–12. [54] Kitajka K, Puskás LG, Zvara A, Hackler Jr L, Barceló-Coblijn G, Yeo YK, et al. The role of n-3 polyunsaturated fatty acids in brain: modulation of rat brain gene expression by dietary n-3 fatty acids. Proc Natl Acad Sci USA 2002;99:2619–24. [55] Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci USA 1995;92:8856–60. [56] Kotani S, Nakazawa H, Tokimasa T, Akimoto K, Kawashima H, Toyoda-Ono Y, et al. Synaptic plasticity preserved with arachidonic acid diet in aged rats. Neurosci Res 2003;46:453–61. [57] Kotarsky K, Nilsson NE, Flodgren E, Owman C, Olde B. A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem Biophys Res Commun 2003;301:406–10. [58] Liu JW, Almaguel FG, Bu L, De Leon DD, De Leon M. Expression of E-FABP in PC12 cells increases neurite extension during differentiation: involvement of n23 and n26 fatty acids. J Neurochem 2008;106:2015–29. [59] Lonze BE, Ginty DD. Function and regulation of CREB family transcription factors in the nervous system. Neuron 2002;35:605–23. [60] Lynch MA. Age-related impairment in long-term potentiation in hippocampus: a role for the cytokine, interleukin-1b? Prog Neurobiol 1998;56:571–89. [61] Ma D, Tao B, Warashina S, Kotani S, Lu L, Kaplamadzhiev DB, et al. Expression of free fatty acid receptor GPR40 in the CNS of adult monkeys. Neurosci Res 2007;58:394–401. [62] Ma D, Lu L, Boneva NB, Warashina S, Kaplamadzhiev DB, Mori Y, et al. Expression of free fatty acid receptor GPR40 in the neurogenic niche of adult monkey hippocampus. Hippocampus 2008;18:326–33. [63] Ma D, Zhang M, Larsen CP, Xu F, Hua W, Yamashima T, et al. DHA promotes the neuronal differentiation of rat neural stem cells transfected with GPR40 gene. Brain Res 2010;1330:1–8. [64] Madsen TM, Treschow A, Bengzon J, Bolwig TG, Lindvall O, Tingström A. Increased neurogenesis in a model of electroconvulsive therapy. Biol Psychiatry 2000;47:1043–9. [65] Maingret F, Fosset M, Lesage F, Lazdunski M, Honoré E. TRAAK is a mammalian neuroneal mechano-gated K+ channel. J Biol Chem 1999; 274:1381–7. [66] Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000; 20:9104–10. [67] Maller JL. Signal transduction. Fishing at the cell surface. Science 2003;300:594–5. [68] Martin RE, Bazan NG. Changing fatty acid content of growth cone lipids prior to synaptogenesis. J Neurochem 1992;59:318–25. [69] McGahon B, Clements MP, Lynch MA. The ability of aged rats to sustain longterm potentiation is restored when the age-related decrease in membrane arachidonic acid concentration is reversed. Neuroscience 1997;81:9–16. [70] Merz K, Herold S, Lie DC. CREB in adult neurogenesis – master and partner in the development of adult-born neurons? Eur J Neurosci 2011;33:1078–86. [71] Moll JR, Acharya A, Gal J, Mir AA, Vinson C. Magnesium is required for specific DNA binding of the CREB B-ZIP domain. Nucleic Acids Res 2002;30:1240–6.

T. Yamashima / Progress in Lipid Research 51 (2012) 221–231 [72] Mukherjee PK, Marcheselli VL, Serhan CN, Bazan NG. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci USA 2004;101:8491–6. [73] Muskiet FA, Fokkema MR, Schaafsma A, Boersma ER, Crawford MA. Is docosahexaenoic acid (DHA) essential? Lessons from DHA status regulation, our ancient diet, epidemiology and randomized controlled trials. J Nutr 2004;134:183–6. [74] Nair A, Vaidya VA. Cyclic AMP response element binding protein and brainderived neurotrophic factor: molecules that modulate our mood? J Biosci 2006;31:423–34. [75] Nakagawa S, Kim JE, Lee R, Malberg JE, Chen J, Steffen C, et al. Regulation of neurogenesis in adult mouse hippocampus by cAMP and cAMP response element-binding protein. J Neurosci 2002;22:3673–82. [76] Nakagawa S, Kim JE, Lee R, Chen J, Fujioka T, Malberg J, et al. Localization of phosphorylated cAMP response element-binding protein in immature neurons of adult hippocampus. J Neurosci 2002;22:9868–76. [77] Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 1995;15:7539–47. [78] Niu SL, Mitchell DC, Lim SY, Wen ZM, Kim HY, Salem Jr N, et al. Reduced G protein-coupled signaling efficiency in retinal rod outer segments in response to n-3 fatty acid deficiency. J Biol Chem 2004;279:31098–104. [79] Nunez EA. Biological complexity is under the ‘strange attraction’ of nonesterified fatty acids. Prostaglandins Leukot Essent Fatty Acids 1997;57:107–10. [80] Owada Y. Fatty acid binding protein: localization and functional significance in the brain. Tohoku J Exp Med 2008;214:213–20. [81] Poo MM. Neurotrophins as synaptic modulators. Nat Rev Neurosci 2001;2:24–32. [82] Price PT, Nelson CM, Clarke SD. Omega-3 polyunsaturated fatty acid regulation of gene expression. Curr Opin Lipidol 2000;11:3–7. [83] Rao JS, Ertley RN, Lee HJ, DeMar Jr JC, Arnold JT, Rapoport SI, et al. n-3 Polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism. Mol Psychiatry 2007;12:36–46. [84] Rapoport SI. In vivo fatty acid incorporation into brain phospholipids in relation to plasma availability, signal transduction and membrane remodelling. J Mol Neurosci 2001;16:243–61. [85] Rapoport SI, Rao JS, Igarashi M. Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver. Prostaglandins Leukot Essent Fatty Acids 2007;77:251–61. [86] Riccio A, Ahn S, Davenport CM, Blendy JA, Ginty DD. Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science 1999;286:2358–61. [87] Rizo J, Sudhof TC. SNAREs and Munc18 in synaptic vesicle fusion. Nat Rev Neurosci 2002;3:641–53. [88] Robson LG, Dyall S, Sidloff D, Michael-Titus AT. Omega-3 polyunsaturated fatty acids increase the neurite outgrowth of rat sensory neurons throughout development and in aged animals. Neurobiol Aging 2010;31:678–87. [89] Rosenbaum DM, Rasmussen SGF, Kobilka BK. The structure and function of Gprotein-coupled receptors. Nature 2009;459:356–63. [90] Sakamoto T, Cansev M, Wurtman RJ. Oral supplementation with docosahexaenoic acid and uridine-5-monophosphate increases dendritic spine density in adult gerbil hippocampus. Brain Res 2007;1182:50–9.

231

[91] Salem Jr N, Litman B, Kim HY, Gawrisch K. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 2001;36:945–59. [92] Sarau HM, Ames RS, Chambers J, et al. Identification, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor. Mol Pharmacol 1999;56:657–63. [93] Sastry PS. Lipids of nervous tissue: composition and metabolism. Prog Lipid Res 1985;242:69–176 [Review]. [94] Sawzdargo M, George SR, Nguyen T, Xu S, Kolakowski LF, O’Dowd BF. A cluster of four novel human G protein-coupled receptor genes occurring in close proximity to CD22 gene on chromosome 19q13.1. Biochem Biophys Res Commun 1997;239:543–7. [95] Schmidt-Hieber C, Jonas P, Bischofberger J. Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 2004;429:184–7. [96] Seki T, Arai Y. The persistent expression of a highly polysialylated NCAM in the dentate gyrus of the adult rat. Neurosci Res 1991;12:503–13. [97] Seki T, Arai Y. Different PSA–NCAM expression patters in distinct types of mossy fiber boutons in the adult hippocampus. J Comp Neurol 1999;510:115–25. [98] Seki T, Arai Y. The temporal and spacial relationship between PSA–NCAMexpressing newly generated granule cells and radial glia-like cells in the adult dentate gyrus. J Comp Neurol 1999;510:503–13. [99] Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR, Mirick G, et al. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J Exp Med 2002;196:1025–37. [100] Sinclair HM. Deficiency of essential fatty acids and atherosclerosis, etcetera. Lancet 1956;270:381–3. [101] Spector AA, Hoak JC. Fatty acids, platelets, and microcirculatory obstruction. Science 1975;190:490–2. [102] Sprecher H. Metabolism of highly unsaturated n-3 and n-6 fatty acids. Biochim Biophys Acta 2000;1486:219–31. [103] Su HM. Mechanisms of n-3 fatty acid-mediated development and maintenance of learning memory performance. J Nutr Biochem 2010;21:364–73. [104] Suh H, Deng W, Gage FH. Signaling in adult neurogenesis. Annu Rev Cell Dev Biol 2009;25:253–75. [105] Tanabe Y, Hashimoto M, Sugioka K, Maruyama M, Fujii Y, Hagiwara R, et al. Improvement of spatial cognition with dietary docosahexaenoic acid is associated with an increase in Fos expression in rat CA1 hippocampus. Clin Exp Pharmacol Physiol 2004;3110:700–3. [106] Van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 1999;2:266–70. [107] Wang ZJ, Liang CL, Li GM, Yu CY, Yin M. Neuroprotective effects of arachidonic acid against oxidative stress on rat hippocampal slices. Chem Biol Inter 2006;163:207–17. [108] Wu GY, Deisseroth K, Tsien RW. Activity-dependent CREB phosphorylation: convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Proc Natl Acad Sci USA 2001;98:2808–13. [109] Yamashima T. A putative link of PUFA, GPR40 and adult-born hippocampal neurons for memory. Prog Neurobiol 2008;84:105–15.