Postsynaptic Serine Racemase Regulates NMDA Receptor Function

Wong, Jonathan; Folorunso, Oluwarotimi; Barragan, Eden V.; Berciu, Cristina; Harvey, Theresa L.; Coyle, Joseph T.; Balu, Darrick T.; Gray, John A.

doi:10.1523/jneurosci.1525-20.2020

Cited by 43 publications

(28 citation statements)

References 74 publications

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“…More recent studies, using the SRKO mice as controls, have (53,(77)(78)(79)(80)(81)(82)(83)(84). Furthermore, in agreement with previous studies in cultured neurons (85,86), we recently reported that SR localizes to the apical dendrites and the post-synaptic density in situ in hippocampal CA1 pyramidal neurons and regulates postsynaptic NMDARs (64). Importantly, while conditional knockout (cKO) of SR from astrocytes has minimal impact on SR levels, cKO from CaMKIIa-expressing forebrain glutamatergic neurons results in $65% reduction of SR expression in the cortex and hippocampus (59).…”

Section: Deletion Of Sr From Ca1 Pyramidal Neurons Results In a Cell-autonomous Reduction In Gabaergic Synapsessupporting

confidence: 90%

“…The lack of apparent seizure activity with the increase E/I ratio further suggests concurrent homeostatic processes, though we cannot rule out covert temporal lobe epileptiform bursting in the SRKO mice. Furthermore, other compensatory mechanisms could contribute to the normalization of LTP in the SRKO mice, including an increase in hippocampal glycine levels (109), and an increased in synaptic GluN2B (53,64). Overall, these homeostatic changes suggest that there is a prioritization of synaptic and cellular functions over network function resulting in a disruption of the signalto-noise ratio and impairing cognition.…”

Section: Discussionmentioning

confidence: 99%

“…Neonatal [P0] SR fl mice of both sexes were stereotaxically injected with a low-titer rAAV1-Cre:GFP viral stock ($1 Â 10 12 vg/mL) targeting hippocampal CA1 as previously described (61,62), resulting in very sparse transduction of CA1 pyramidal cells. At 2-3 mo, the injected mice were anesthetized with isoflurane and transcardially perfused with ice-cold artificial cerebrospinal fluid (ACSF), containing ( (63) for 15 min, which we have previously used to increase cell health in slices from older animals (64). Slices were transferred to room temperature ACSF and held for at least 1 h before recording.…”

Section: Single Neuron Sr Deletion Experimentsmentioning

confidence: 99%

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Increased excitation-inhibition balance and loss of GABAergic synapses in the serine racemase knockout model of NMDA receptor hypofunction

Jami

Cameron

Wong

et al. 2021

Journal of Neurophysiology

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There is substantial evidence that both NMDA receptor (NMDAR) hypofunction and dysfunction of GABAergic neurotransmission contribute to schizophrenia, though the relationship between these pathophysiological processes remains largely unknown. While models using cell-type-specific genetic deletion of NMDARs have been informative, they display overly pronounced phenotypes extending beyond those of schizophrenia. Here, we used the serine racemase knockout (SRKO) mice, a model of reduced NMDAR activity rather than complete receptor elimination, to examine the link between NMDAR hypofunction and decreased GABAergic inhibition. The SRKO mice, in which there is a >90% reduction in the NMDAR co-agonist d-serine, exhibit many of the neurochemical and behavioral abnormalities observed in schizophrenia. We found a significant reduction in inhibitory synapses onto CA1 pyramidal neurons in the SRKO mice. This reduction increases the excitation/inhibition balance resulting in enhanced synaptically-driven neuronal excitability without changes in intrinsic excitability. Consistently, significant reductions in inhibitory synapse density in CA1 were observed by immunohistochemistry. We further show, using a single-neuron genetic deletion approach, that the loss of GABAergic synapses onto pyramidal neurons observed in the SRKO mice is driven in a cell-autonomous manner following the deletion of SR in individual CA1 pyramidal cells. These results support a model whereby NMDAR hypofunction in pyramidal cells disrupts GABAergic synapses leading to disrupted feedback inhibition and impaired neuronal synchrony.

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Section: Deletion Of Sr From Ca1 Pyramidal Neurons Results In a Cell-autonomous Reduction In Gabaergic Synapsessupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Single Neuron Sr Deletion Experimentsmentioning

confidence: 99%

See 1 more Smart Citation

Increased excitation-inhibition balance and loss of GABAergic synapses in the serine racemase knockout model of NMDA receptor hypofunction

Jami

Cameron

Wong

et al. 2021

Journal of Neurophysiology

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“…Our observation of increased synaptic enrichment of NMDARs relative to WT within the hippocampus is expected based on previous studies on SRKO mice showing increased expression of GluN1 (37,38) and GluN2B (23,51). These changes in the overall number and composition of NMDARs are likely to be the consequence of lack of D-serine, as prior studies have demonstrated the role of co-agonist binding in priming of the NMDAR for endocytosis, with D-serine specifically acting on GluN2B subunits (52,53).…”

Section: Discussionsupporting

confidence: 81%

Reduced D-serine levels drive enhanced non-ionotropic NMDA receptor signaling and destabilization of dendritic spines in a mouse model for studying schizophrenia

Ev³

et al. 2021

Preprint

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Schizophrenia is a psychiatric disorder that affects over 20 million people globally. Notably, schizophrenia is associated with decreased density of dendritic spines and decreased levels of D-serine, a co-agonist of the N-methyl-D-aspartate receptor (NMDAR), and hypofunction of NMDARs is thought to play a role in the pathophysiology of schizophrenia. We hypothesized that lowered D-serine levels associated with schizophrenia would bias toward ion flux-independent signaling by the NMDAR, which drives spine shrinkage and loss. Using a schizophrenia mouse model lacking the enzyme for D-serine production (serine racemase knock out; SRKO), we show that activity-dependent spine growth is inhibited in SRKO mice but can be acutely rescued by exogenous D-serine. When examining a wider range of stimulus strengths, we observed activity-dependent spine growth at higher stimulus strengths, but overall found a strong bias toward spine shrinkage in the SRKO mice as compared to wild-type littermates. Furthermore, we demonstrate that enhanced ion flux-independent signaling through the NMDAR contributes to this bias toward spine shrinkage, which is likely exacerbated by an increase in synaptic NMDARs in hippocampal synapses of SRKO mice. Our results support a model in which the lowered D-serine levels associated with schizophrenia lead to increased ion flux-independent NMDAR signaling and a bias toward spine shrinkage that could play an important role in the loss of dendritic spines associated with schizophrenia.

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“…For example, there is an apparent discrepancy regarding changes in synaptic plasticity and NMDAR activation at CA3/CA1 hippocampal synapses. On one hand, studies of isolated excitatory glutamate transmission on CA1 pyramidal cells reported LTP deficits and altered NMDAR activation in slices from SR-KO mice [ 23 , 26 , 27 ]. On the other hand, extracellular recordings that monitor the overall network activity did not show differences in LTP [ 10 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Serine Racemase Deletion Affects the Excitatory/Inhibitory Balance of the Hippocampal CA1 Network

Bouët

Radzishevsky

Wolosker

et al. 2020

IJMS

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d-serine is the major co-agonist of N-methyl-D-aspartate receptors (NMDAR) at CA3/CA1 hippocampal synapses, the activation of which drives long-term potentiation (LTP). The use of mice with targeted deletion of the serine racemase (SR) enzyme has been an important tool to uncover the physiological and pathological roles of D-serine. To date, some uncertainties remain regarding the direction of LTP changes in SR-knockout (SR-KO) mice, possibly reflecting differences in inhibitory GABAergic tone in the experimental paradigms used in the different studies. On the one hand, our extracellular recordings in hippocampal slices show that neither isolated NMDAR synaptic potentials nor LTP were altered in SR-KO mice. This was associated with a compensatory increase in hippocampal levels of glycine, another physiologic NMDAR co-agonist. SR-KO mice displayed no deficits in spatial learning, reference memory and cognitive flexibility. On the other hand, SR-KO mice showed a weaker LTP and a lower increase in NMDAR potentials compared to controls when GABAA receptors were pharmacologically blocked. Our results indicate that depletion of endogenous D-serine caused a reduced inhibitory activity in CA1 hippocampal networks, altering the excitatory/inhibitory balance, which contributes to preserve functional plasticity at synapses and to maintain related cognitive abilities.

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Postsynaptic Serine Racemase Regulates NMDA Receptor Function

Cited by 43 publications

References 74 publications

Increased excitation-inhibition balance and loss of GABAergic synapses in the serine racemase knockout model of NMDA receptor hypofunction

Increased excitation-inhibition balance and loss of GABAergic synapses in the serine racemase knockout model of NMDA receptor hypofunction

Reduced D-serine levels drive enhanced non-ionotropic NMDA receptor signaling and destabilization of dendritic spines in a mouse model for studying schizophrenia

Serine Racemase Deletion Affects the Excitatory/Inhibitory Balance of the Hippocampal CA1 Network

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