Aging-Associated Cognitive Decline is Reversed by D-Serine Supplementation

Nava-Gomez, Laura J.; Calero-Vargas, Isnarhazni; Higinio-Rodríguez, Frida; Vázquez-Prieto, B; Olivares-Moreno, Rafael; Ortíz-Retana, Juan José; Aranda, P; Hernandez-Chan, Nancy G.; Rojas-Piloni, Gerardo; Alcauter, Sarael; López‐Hidalgo, Mónica

doi:10.1523/eneuro.0176-22.2022

Cited by 13 publications

(6 citation statements)

References 113 publications

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“…In addition, dynamic interactions between the OFC and hippocampus for reversal learning have been noted, with local field potentials of the OFC and hippocampus exhibiting coherence in theta rhythm in a performancedependent manner [78,79] and contralateral lesions of the OFC and ventral hippocampus in mice subtly, though significantly, impairing spatial reversal learning [78]. Systemic D-serine treatment has shown beneficial effects on spatial reversal learning [69,[80][81][82][83]. However, for this study, upregulation of SR in the mPFC did not affect reversal.…”

Section: Discussionmentioning

confidence: 99%

Viral vector-mediated upregulation of serine racemase expression in medial prefrontal cortex improves learning and synaptic function in middle age rats

Yegla

Rani

Kumar

2023

Aging

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An age-associated decrease in N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic function contributes to impaired synaptic plasticity and is associated with cognitive impairments. Levels of serine racemase (SR), an enzyme that synthesizes D-serine, an NMDAR co-agonist, decline with age. Thus, enhancing NMDAR function via increased SR expression in middle age, when subtle declines in cognition emerge, was predicted to enhance performance on a prefrontal cortex-mediated task sensitive to aging. Middle-aged (~12 mo) male Fischer-344 rats were injected bilaterally in the medial prefrontal cortex (mPFC) with viral vector (LV), SR (LV-SR) or control (LV-GFP). Rats were trained on the operant attentional set-shift task (AST) to examine cognitive flexibility and attentional function. LV-SR rats exhibited a faster rate of learning compared to controls during visual discrimination of the AST. Extradimensional set shifting and reversal were not impacted. Immunohistochemical analyses demonstrated that LV-SR significantly increased SR expression in the mPFC. Electrophysiological characterization of synaptic transmission in the mPFC slices obtained from LV-GFP and LV-SR animals indicated a significant increase in isolated NMDAR-mediated synaptic responses in LV-SR slices. Thus, results of the current study demonstrated that prefrontal SR upregulation in middle age rats can improve learning of task contingencies for visual discrimination and increase glutamatergic synaptic transmission, including NMDAR activity.

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Section: Discussionmentioning

confidence: 99%

Viral vector-mediated upregulation of serine racemase expression in medial prefrontal cortex improves learning and synaptic function in middle age rats

Yegla

Rani

Kumar

2023

Aging

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“…(d) The NMDA receptor surface expression and its functions also alter with age. NMDA receptor hypofunction, as well as a decline of calcium entry via NMDA receptors were reported in elderly (Foster, 2007;Nava-Gómez et al, 2022).…”

Section: Sics and Sic-dependent Changes In Synaptic Strength Are Affe...mentioning

confidence: 99%

Astrocyte‐ and NMDA receptor‐dependent slow inward currents differently contribute to synaptic plasticity in an age‐dependent manner in mouse and human neocortex

Csemer,

Kovács,

Maamrah

et al. 2023

Aging Cell

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Slow inward currents (SICs) are known as excitatory events of neurons elicited by astrocytic glutamate via activation of extrasynaptic NMDA receptors. By using slice electrophysiology, we tried to provide evidence that SICs can elicit synaptic plasticity. Age dependence of SICs and their impact on synaptic plasticity was also investigated in both on murine and human cortical slices. It was found that SICs can induce a moderate synaptic plasticity, with features similar to spike timing‐dependent plasticity. Overall SIC activity showed a clear decline with aging in humans and completely disappeared above a cutoff age. In conclusion, while SICs contribute to a form of astrocyte‐dependent synaptic plasticity both in mice and humans, this plasticity is differentially affected by aging. Thus, SICs are likely to play an important role in age‐dependent physiological and pathological alterations of synaptic plasticity.

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“…Regulating D-serine levels through SR can be a novel drug target for the treatment of neurotoxic disorders like stroke and traumatic brain injury or neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and late-stage Alzheimer's disease (AD) with elevated D-serine [8][9][10][11][12][13][14]. At the same time, treatment with an NMDA receptor agonist, D-serine alone, or D-serine combined with a glycine reuptake inhibitor has been demonstrated to improve the psychotic symptoms and cognition in patients with schizophrenia, depression, early-stage AD, and agingassociated cognitive decline [7,[15][16][17][18]. In a double-blind crossover clinical trial, D-serine treatment could alleviate symptoms of schizophrenia and depression [19].…”

Section: Nmda Receptor Dysfunction and Its Potential Drug Targetmentioning

confidence: 99%

The Development of a Regulator of Human Serine Racemase for N-Methyl-D-aspartate Function

Lu,

Chang,

Mao

et al. 2024

Biomedicines

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It is crucial to regulate N-methyl-D-aspartate (NMDA) function bivalently depending on the central nervous system (CNS) conditions. CNS disorders with NMDA hyperfunction are involved in the pathogenesis of neurotoxic and/or neurodegenerative disorders with elevated D-serine, one of the NMDA receptor co-agonists. On the contrary, NMDA-enhancing agents have been demonstrated to improve psychotic symptoms and cognition in CNS disorders with NMDA hypofunction. Serine racemase (SR), the enzyme regulating both D- and L-serine levels through both racemization (catalysis from L-serine to D-serine) and β-elimination (degradation of both D- and L-serine), emerges as a promising target for bidirectional regulation of NMDA function. In this study, we explored using dimethyl malonate (DMM), a pro-drug of the SR inhibitor malonate, to modulate NMDA activity in C57BL/6J male mice via intravenous administration. Unexpectedly, 400 mg/kg DMM significantly elevated, rather than decreased (as a racemization inhibitor), D-serine levels in the cerebral cortex and plasma. This outcome prompted us to investigate the regulatory effects of dodecagalloyl-α-D-xylose (α12G), a synthesized tannic acid analog, on SR activity. Our findings showed that α12G enhanced the racemization activity of human SR by about 8-fold. The simulated and fluorescent assay of binding affinity suggested a noncooperative binding close to the catalytic residues, Lys56 and Ser84. Moreover, α12G treatment can improve behaviors associated with major CNS disorders with NMDA hypofunction including hyperactivity, prepulse inhibition deficit, and memory impairment in animal models of positive symptoms and cognitive impairment of psychosis. In sum, our findings suggested α12G is a potential therapeutic for treating CNS disorders with NMDA hypofunction.

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Aging-Associated Cognitive Decline is Reversed by D-Serine Supplementation

Cited by 13 publications

References 113 publications

Viral vector-mediated upregulation of serine racemase expression in medial prefrontal cortex improves learning and synaptic function in middle age rats

Viral vector-mediated upregulation of serine racemase expression in medial prefrontal cortex improves learning and synaptic function in middle age rats

Astrocyte‐ and NMDA receptor‐dependent slow inward currents differently contribute to synaptic plasticity in an age‐dependent manner in mouse and human neocortex

The Development of a Regulator of Human Serine Racemase for N-Methyl-D-aspartate Function

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