d -Serine in the aging hippocampus

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Review

d-Serine in the aging hippocampus Jean-Marie Billard ∗ Center of Psychiatry and Neurosciences, Paris Descartes University, Sorbonne Paris City, UMR U894, Paris 75014 France

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Article history: Received 3 November 2014 Received in revised form 3 February 2015 Accepted 7 February 2015 Available online xxx Keywords: Aging Memory NMDA receptors CA3/CA1 synapses Dentate gyrus

a b s t r a c t Experimental evidences now indicate that memory formation relies on the capacity of neuronal networks to manage long-term changes in synaptic communication. This property is driven by N-methyl-daspartate receptors (NMDAR), which requires the binding of glutamate but also the presence of the co-agonist d-serine at the glycine site. Defective memory function and impaired brain synaptic plasticity observed in aging are rescued by partial agonist acting at this site suggesting that this gating process is targeted to induce age-related cognitive defects. This review aims at compelling recent studies characterizing the role of d-serine in changes in functional plasticity that occur in the aging hippocampus since deficits are rescued by d-serine supplementation. The impaired efficacy of endogenous d-serine is not due to changes in the affinity to glycine-binding site but to a decrease in tissue levels of the amino acid resulting from a weaker expression of the producing enzyme serine racemase (SR). Interestingly, neither SR expression, d-serine levels, nor NMDAR activation is affected in aged LOU/C rats, a model of healthy aging in which memory deficits do not occur. These old animals do not develop oxidative stress suggesting that the d-serine-related pathway could be targeted by the age-related accumulation of reactive oxygen species. Accordingly, senescent rats chronically treated with the reducing agent N-acetyl-cysteine to prevent oxidative damage, show intact NMDAR activation linked to preserved d-serine levels and SR expression. These results point to a significant role of d-serine in age-related functional alterations underlying hippocampus-dependent memory deficits, at least within the CA1 area since the amino acid does not appear as critical in changes affecting the dentate gyrus. © 2015 Published by Elsevier B.V.

Contents 1. 2. 3. 4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Age-related changes in NMDAR-dependent synaptic plasticity in CA1 hippocampal area: determination of d-serine and mechanisms affecting d-serine-dependent action on glycine-binding site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Age-related alteration of the d-serine-related pathway: a role for oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regional susceptibility within the hippocampal formation of the d-serine-related pathway to aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Although physiological aging is associated to subtle brain alterations compared to pathological conditions such as Alzheimer’s disease [1,2], it is commonly associated with a decline in learning

∗ Correspondence to: Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris cité, UMR894, 2 ter rue d’Alésia, 75014 Paris, France. Tel.: +33 140788647; fax: +33 1145807293. E-mail address: [email protected]

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and memory, particularly for newly acquired information [3]. Clinical reports indicate that the hippocampal formation is most frequently involved in the age-related memory dysfunction while experimental studies on animal models show that functional properties of hippocampal neuronal networks are vulnerable to the process of aging (see [4] for a review). In particular, results from electrophysiological studies conducted both in vivo and ex vivo [5–7] show clear cut alterations with age of the threshold and/or the magnitude of long-term potentiation (LTP) or long-term depression (LTD), that are long lasting changes in synaptic transmission now considered as functional substrates underlying memory

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Fig. 1. Decrease in d-serine synthesis underlies age-related deficits of NMDAR-dependent LTP in hippocampal CA1 region. (A) The impaired theta-burst-induced LTP in CA1 area of aged rats under control conditions (filled triangles) compared to adult rats (empty circles) is rescued in medium supplemented with d-serine (100 ␮M) (gray rhombus) (***P < 0.0001). (B) Bar graphs of the adult/aged ratio of amino acid contents determined in hippocampal tissues indicating that d-serine but not l-serine and glycine levels are decreased in aged rats. (C) Bar graphs showing that protein levels of SR are significantly reduced in aged (black column) compared to adult rats (white column) (**P < 0.001). At the top are illustrated representative immunoblots for ␤-actin (upper band) and SR (lower band). Modified from Ref. [38].

encoding [8,9]. Because the regulation of synaptic strength relies on activation of N-methyl-d-aspartate subtype of glutamate receptors (NMDAR) [10–14], a particular attention has been paid to know whether this process could be altered in the course of aging. Although studies in the last decade repetitively demonstrate that NMDAR activation is impaired in the hippocampal formation of aged rodents [15–18], the underlying mechanisms are still far to be definitively defined. In addition to the gating by glutamate, one specific property underlying NMDAR activation is the necessity of the binding of a co-agonist at the strychnine insensitive glycine site located on GluN1 subunits [19–21]. Studies on age-related changes in synaptic availability of glutamate has led to negative results [22], arguing against the possibility of supplementation with the amino acid as a putative pharmacological strategy to prevent cognitive aging. Concerning the glycine-binding site, the recent use of pharmacological, enzymatic and/or gene invalidation strategies

indicates that the amino acid d-serine, rather than glycine, is the main endogenous co-agonist of NMDAR in cerebral areas involved in memory processes [23–27]. In addition, it has been repetitively shown that d-serine is required for the expression of synaptic plasticity in neuronal networks of both CA1 and dentate gyrus hippocampal subfields [23–29]. This raises the possible contribution of d-serine in changes in functional plasticity taking place in the aging hippocampus, and consequently on the role of the amino acid in age-related memory defects (see [30]). This focused review aims at compelling recent experimental data indicating that the d-serine-related pathway significantly contributes to alterations of NMDAR-dependent synaptic plasticity in hippocampal CA1 region but not in dentate gyrus during normal aging, that could hamper the development of d-serine-related pharmacological therapies to prevent cognitive aging associated to non-pathological conditions.

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2. Age-related changes in NMDAR-dependent synaptic plasticity in CA1 hippocampal area: determination of d-serine and mechanisms affecting d-serine-dependent action on glycine-binding site Electrophysiological studies conducted in CA1 area of hippocampal slices show that high-frequency conditioning stimulation of glutamate inputs induces a long-term potentiation (LTP) of excitatory synaptic transmission in adult rats and mice but not in aged animals impaired in behavior-tested memory tasks [17,31–34]. In those animals, the stimulation-induced increase in synaptic strength rapidly returns to baseline levels and is thus unable to be converted onto subsequent LTP (Fig. 1A). Importantly, supplementation of the slices with d-serine occludes this functional defect allowing LTP to be expressed (Fig. 1A). Such a rescue by exogenously applied co-agonist is observed for several forms of synaptic plasticity including theta-burst- and high frequency stimulation-induced LTP [35–38] but also low frequency stimulation (LFS)-induced long term depression (LTD) and depotentiation [39,40], which are all types of functional plasticity impaired in the aging brain [6,41,42]. The rescue by the NMDAR co-agonist is not species-dependent since a similar supplementation with d-serine is also able to reverse the age-related deficits in thetaburst stimulation-induced LTP in senescence-accelerated prone/8 (SAMP8) mice [29]. Because activation of the NMDAR glycine-binding site by dserine is mandatory for the induction of synaptic plasticity [23–29], the LTP rescue observed in aged animals after supplementation with the co-agonist suggests that the gating managed by endogenous d-serine is altered with age. Accordingly, the age-related defect of pharmacologically isolated NMDAR-dependent synaptic potentials repetitively demonstrated in aged rodents [15,16,18,43] is reversed after saturating glycine-binding sites with d-serine or with the related agonist d-cycloserine [36–39]. Because the rescue of NMDAR potentials by these compounds is complete, it may be argued that changes in co-agonist-related pharmacological properties account for the age-related impairment of NMDAR activation rather than the decrease in receptor density initially proposed as the main underlying mechanism [44,45]. Interestingly, the potency of exogenous d-serine to enhance NMDAR activation appears significantly higher in slices from aged rats [36,40] when compared to effects in adult animals [46,47]. Such an increased efficacy of d-serine supplementation with age could reflect changes in the degree of receptor saturation determined by the specific affinity of the glycine-binding site and/or changes in endogenous levels of the co-agonist. Autoradiography binding studies performed in the hippocampus of aged rats and mice do not find any modifications of the affinity of d-serine to the glycine-binding site [37,48]. On the contrary, a decrease in levels of endogenous d-serine occurs in hippocampal tissues of old animals as characterized by high-performance liquid chromatography (HPLC) analysis [35,38] (Fig. 1B). In these experiments, free d-serine was extracted from pooled hippocampal tissues of young and aged rats with trichloroacetic acid according to published procedures [49]. HPLC analysis was performed by a pre-column derivatization of samples using O-phthaldialdehyde and N-acetyl cysteine and diasteroisomers were resolved in isocratic phase on a C18 novapak column. The amount of d-serine was adjusted to content of proteins determined by a Dc protein Bio-Rad (Bio-Rad Laboratories). Standards of d-serine were used to normalize results. These results differ from earlier studies which did not report any changes in levels of the co-agonist in whole brain extracts [48,50] indicating that modifications of d-serine concentrations probably occur in restricted area of the aging brain. While the amount of dserine decreases in the aging hippocampus, levels of the precursor l-serine slightly increases at the same time (Fig. 1B) suggesting that

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the biosynthesis pathway of the co-agonist is affected. Accordingly, the expression of serine racemase (SR) that converts l-serine into d-serine [51,52], is weakened in CA1 area of aged rats both at protein and messenger RNA levels [35,37,38] (Fig. 1C) but it remains to be known whether the activity of the enzyme is altered at the same time. Interestingly, age-related changes in SR expression are not found in cerebral cortex and cerebellum [38] reinforcing the idea that the reduction of d-serine levels must occur in confined area of the aging brain. On the other hand, the expression of the metabolizing enzyme d-amino acid oxidase (DAAO) is not affected in aged animals ruling out the possibility that the age-associated decrease in d-serine levels relies on an exaggerated degradation of the amino acid [37,40]. By compelling these data, it appears that the functional plasticity driving by d-serine needs to be preserved in CA1 hippocampal networks to maintain the expression of potent memory capacities in aging. According to this postulate, it is worth noting that the targeted disruption of SR affects memory abilities as well as the expression of synaptic plasticity, confirming a critical role of dserine in brain mechanisms governing cognition [23,53–55]. Such a critical role of the amino acid in cognitive aging has recently been confirmed by studies performed on the inbred LOU/C rat

Fig. 2. d-Serine-mediated synaptic plasticity is preserved in hippocampal CA1 region of aged LOU/C rats. (A) Bar graphs showing that protein levels of SR are similar in aged (black column) compared to adult rats (white column) in hippocampal tissues. At the top are illustrated representative immunoblots for ␤-actin (upper band) and SR (lower band). (B) The theta-burst-induced LTP in CA1 hippocampal area is comparable in slices from adult (empty squares) and aged (filled rhombus) LOU/C rats. Modified from Ref. [38].

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Fig. 3. Preventing oxidative stress alleviates age-related deficits of d-serine-mediated synaptic plasticity. (A) Bar graphs showing that long-term dietary with l-NAC rescues the oxidative stress in the hippocampus of aged rats as illustrated by the reversal of the decrease in GSH/GSSG ratio and of the increase in levels of carbonylated proteins (**P < 0.001). (B) Bar graphs indicating that hippocampal protein levels of SR are similar in l-NAC treated aged rats (black column) compared to adult animals (white column). (C) Bar graphs of hippocampal d-serine levels showing that high amount of the co-agonist are maintained in l-NAC treated aged rats (**P < 0.001 and ***P < 0.0001). (D) The time course and the magnitude of theta-burst-induced LTP in CA1 area are identical in slices from adult (empty circles) and l-NAC treated aged rats (filled triangles). Modified from Ref. [35].

which displays many assets (no insulino- and leptino-resistance, low growth hormone and IGF1 production, preserved cerebrovascular hemodynamics, etc.) to constitute a model of healthy aging [56–58]. Behavioral investigations indicate that LOU/C rats, which show an increased median lifespan (50% of survivors) compared to other strains of rats, do not develop deficits of hippocampaldependent memory at very advanced ages [59–61]. Investigations of the d-serine-related metabolic pathway and functional plasticity in the brain of young and aged LOU/C rats have gained further insights into the significant contribution of the NMDAR co-agonist

into cognitive aging. Indeed, SR expression and d-serine availability are not affected in hippocampal tissues of aged LOU/C rats (Fig. 2A) while ex vivo electrophysiological recordings in CA1 hippocampal slice preparations indicate that the d-serine gating of NMDA-R-dependent functional plasticity is preserved at the same time [38,59] (Fig. 2B). Importantly, the expression of GluN2 subunits of NMDAR is significantly reduced in aged LOU/C rats despite the fact that memory capacities are preserved [59] confirming that changes in NMDAR density do not correlate with modifications of cognitive abilities in aging.

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Fig. 4. d-Serine does not significantly contribute to age-related LTP impairment in the dentate gyrus. (A) Theta-burst-induced LTP is impaired in the dentate gyrus of slices from aged rats under control conditions (**P < 0.001). (B) Also in control medium, the magnitude of NMDAR-dependent synaptic potentials is reduced in old animals (*P < 0.05). (C) and (D) Supplementation with d-serine does not alleviate age-related deficits of both LTP and NMDAR activation indicating a minor role of the co-agonist at perforant path-granule cell synapses. Modified from Ref. [77].

3. Age-related alteration of the d-serine-related pathway: a role for oxidative stress Although studies conducted in LOU/C rats raise the concept that the d-serine-related pathway and more particularly the expression and/or activity of SR, is a prime target for age-related processes to alter memory performances [62], the exact nature of these triggering processes remained obscure. One striking feature of LOU/C rats consists in a reduced and stable adipose-tissue mass throughout life because these animals spontaneously decrease their energy intake, at least by 40% compared to the other strains of rats [63]. Among other strategies, a decrease in caloric intake has been proposed to reduce cognitive aging [43,64], by limiting the accumulation of reactive oxygen species (ROS) and therefore the extent of oxidative stress (OS) that normally takes place in the aging brain [65]. The ratio of the reduced (GSH) over oxidative (GSSG) forms of the potent endogenous ROS scavenger glutathione represents an index of OS, that decreases in cerebral tissues of aged animals [66,67]. Interestingly, the GSH/GSSG ratio increases in aged LOU/C indicating that age-related OS is totally reversed in those animals. Consequently, ROS accumulation could be viewed as major process acting on the d-serine-related pathway in the aging hippocampus, particularly considering that SR activity that produces the NMDAR co-agonist, is particularly sensitive to nitric oxide-mediated S-nitrosylation [68] and sulfhydryl oxidation [51]. This role of ROS accumulation in triggering age-related defects of brain functionality driven by d-serine has been recently confirmed following chronic dietary manipulation with the reducing agent N-acetyl-l-cysteine (l-NAC) [69]. When delivered from middle-age to senescence [35], this manipulation prevents OS to occur in brain tissues of old rats as illustrated by the increase in GSH/GSSG ratio and also by the reversal of the increase in levels of carbonylated proteins (Fig. 3A), another index of enhanced oxidation in aged cerebral tissues [35]. Importantly, biochemical assays of hippocampal tissues from lNAC-treated aged animals reveal that SR expression (Fig. 3B) and

high d-serine levels (Fig. 3C) are preserved while electrophysiological recordings indicate that NMDAR activation and LTP expression are similar in CA1 hippocampal networks to those recorded in adult animals [35] (Fig. 3D). Even it remains to know whether such a chronic treatment with l-NAC also protects against age-related hippocampal-related memory deficits, these data provide clear evidence that maintaining elevated d-serine levels in the aging hippocampus through the control of the redox state is able to prevent injuries of the cellular mechanisms underlying cognitive aging, at least in CA1 hippocampal area [62]. 4. Regional susceptibility within the hippocampal formation of the d-serine-related pathway to aging In order to elaborate new relevant d-serine-related pharmacological strategies against cognitive aging, determining the mechanisms affecting the availability of the co-agonist is a critical step, but one has also to know if the amino acid significantly contributes to impaired functional plasticity at synapses of the entire aging hippocampus. In fact, LTP deficits occur in both the CA1 region and dentate gyrus of aged rodents [32,36,70–75] (see Fig. 4A), but whether they share similar mechanisms remains poorly documented [76]. d-Serine has a predominant role in driving NMDAR-dependent synaptic plasticity throughout the hippocampus since enzymatically- or genetically-driven loss of the amino acid alters NMDAR synaptic potentials and LTP induction also at perforant path-granule cells synapses of the dentate gyrus [53,77]. However, supplementation with saturating concentrations of dserine does not alleviate LTP deficits displayed by aged animals in this hippocampal area (Fig. 4C) in contrast to what is found in the CA1. Also, the age-related decrease in NMDAR-dependent synaptic potentials (Fig. 4B) is not rescued by the co-agonist (Fig. 4D) indicating a minor role of NMDAR co-agonist in the defect at this level. Instead, the weaker presynaptic glutamatergic inputs from the entorhinal cortex ([78,79], see [1] for a review) and the reduced

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NMDAR density [45,80,81] characterized by morphological and functional analysis, represent the critical mechanisms underlying age-related LTP impairment at perforant path-granule cells synapses [77]. Because SR expression is also decreased within the dentate gyrus during aging (Billard, unpublished results) it could be hypothesized that although d-serine levels are presumably reduced with age in this region, they are still elevated enough to saturate the low NMDAR density expressed at this time [45,80,81], that could prevent the effects of supplementation with the co-agonist. 5. Conclusion The impaired spatial memory in aged rats and the disrupted associative hippocampus-dependent eye-blink conditioning in old rabbits are alleviated by partial agonists acting on the glycinebinding site [82–84]. Consequently, this gating process was originally viewed as a putative target to rescue behavioral defects that occur in aging. The ability of d-serine acting on NMDAR glycine site to rescue age-related deficits of synaptic plasticity had therefore made this amino acid an attractive tool for elaborating pharmacological manipulations to reduce hippocampal-dependent memory dysfunctions associated with aging. Unfortunately, the possibility of long-term treatments with large doses d-serine has been discarded because they cause central side-effects or induce DAAO-dependent necrosis of the terminal portions of the proximal renal tubules [85,86]. The use of low doses of d-serine associated with the DAAO inhibitor CBIO to rescue behavioral deficits due to impaired NMDAR has recently been elaborated [87,88] that could represent an alternative solution. However, the fact that dserine does not significantly contribute to functional deficits at all synapses of the aging hippocampus strongly suggests that only a partial rescue of cognitive aging could be achieved by a treatment with the amino acid, that will hamper the development of pharmacological strategies related to the amino acid. References [1] S.N. Burke, C.A. Barnes, Senescent synapses and hippocampal circuit dynamics, Trends Neurosci. 33 (2010) 153–161. [2] I. Driscoll, D.A. Hamilton, H. Petropoulos, R.A. Yeo, W.M. Brooks, R.N. Baumgartner, R.J. Sutherland, The aging hippocampus: cognitive, biochemical and structural findings, Cereb. Cortex 13 (2003) 1344–1351. [3] J. Jolles, Cognitive, emotional and behavioral dysfunctions in aging and dementia, Prog. Brain Res. 70 (1986) 15–39. [4] J.M. Billard, Ageing, hippocampal synaptic activity and magnesium, Magnes. Res. 19 (2006) 199–215. [5] C.A. Barnes, Long-term potentiation and the ageing brain, Philos. Trans. R. Soc. Lond. B: Biol. Sci. 358 (2003) 765–772. [6] T.C. Foster, Biological markers of age-related memory deficits: treatment of senescent physiology, CNS Drugs 20 (2006) 153–166. [7] M.A. Lynch, Age-related impairment in long-term potentiation in hippocampus: a role for the cytokine, interleukin-1 beta? Prog. Neurobiol. 56 (1998) 571–589. [8] I. Izquierdo, J.H. Medina, Correlation between the pharmacology of long-term potentiation and the pharmacology of memory, Neurobiol. Learn. Mem. 63 (1995) 19–32. [9] S.J. Kim, D.J. Linden, Ubiquitous plasticity and memory storage, Neuron 56 (2007) 582–592. [10] G.L. Collingridge, T.V. Bliss, Memory of NMDA receptors and LTP, Trends Neurosci. 18 (1995) 54–56. [11] B. Gustafsson, H. Wigstrom, Long-term potentiation in the hippocampal CA1 region: its induction and early temporal development, Prog. Brain Res. 83 (1990) 223–232. [12] C.E. Herron, R.A. Lester, E.J. Coan, G.L. Collingridge, Frequency-dependent involvement of NMDA receptors in the hippocamus: a novel synaptic mechanism, Nature 322 (1986) 265–268. [13] R.C. Malenka, R.A. Nicoll, NMDA receptor-dependent synaptic plasticity: multiple forms and mechanisms, Trends Neurosci. 16 (1993) 521–527. [14] R.G. Morris, S. Davis, S.P. Butcher, Hippocampal synaptic plasticity and NMDA receptors: a role in information storage? Philos. Trans. R. Soc. Lond. B: Biol. Sci. 329 (1990) 187–204. [15] C.A. Barnes, G. Rao, J. Shen, Age-related decrease in the N-methyl-d-aspartate R-mediated excitatory postsynaptic potentials in hippocampal region CA1, Neurobiol. Aging 18 (1997) 445–452.

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