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

Jami, Shekib A.; Cameron, Scott A.; Wong, Jonathan; Daly, Emily R; McAllister, A. Kimberley; Gray, John A.

doi:10.1101/2020.09.18.304170

Cited by 6 publications

(11 citation statements)

References 146 publications

(174 reference statements)

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“…Our observations therefore suggest a weaker inhibitory tone in the neuronal networks after the genetic suppression of SR. In agreement, reduced frequency of spontaneous inhibitory postsynaptic currents was recently reported in CA1 pyramidal cells of SR-KO mice [ 31 ], indicating a weaker density of inhibitory synapses, as also supported by a decrease in levels of the vesicular GABA transporter in those animals [ 31 ]. We now raise the possibility that the loss of d -serine in SR-KO mice could also induce a weaker activation of NMDARs present on GABAergic interneurons themselves, thus reducing their inhibitory function.…”

Section: Discussionsupporting

confidence: 87%

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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Section: Discussionsupporting

confidence: 87%

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

Bouët

Radzishevsky

Wolosker

et al. 2020

IJMS

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“…Future studies of SRKO mice can confirm whether (1) the abnormal biomarker phenotypes persist among antipsychotic or D-serine treatment, (2) glycine-related compensatory responses are occurring, (3) thalamocortical circuitry is intact, or (4) abnormalities in dopamine levels, cholinergic signaling, or parvalbumin-containing neurons exist in the neocortex. Recent work indicates SRKO mice have reduced inhibitory tone in hippocampal networks which disrupts neural synchrony and the E/I balance 72,73 . This, along with our gamma band findings support the idea of an E/I imbalance manifested as an aberrant signal-to-noise ratio impairing cognition and information processing.…”

Section: Discussionmentioning

confidence: 99%

Altered neural oscillations and behavior in a genetic mouse model of NMDA receptor hypofunction

Aguilar

Radzik

Schiffino

et al. 2021

Sci Rep

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Abnormalities in electroencephalographic (EEG) biomarkers occur in patients with schizophrenia and those clinically at high risk for transition to psychosis and are associated with cognitive impairment. Converging evidence suggests N-methyl-D-aspartate receptor (NMDAR) hypofunction plays a central role in the pathophysiology of schizophrenia and likely contributes to biomarker impairments. Thus, characterizing these biomarkers is of significant interest for early diagnosis of schizophrenia and development of novel treatments. We utilized in vivo EEG recordings and behavioral analyses to perform a battery of electrophysiological biomarkers in an established model of chronic NMDAR hypofunction, serine racemase knockout (SRKO) mice, and their wild-type littermates. SRKO mice displayed impairments in investigation-elicited gamma power that corresponded with reduced short-term social recognition and enhanced background (pre-investigation) gamma activity. Additionally, SRKO mice exhibited sensory gating impairments in both evoked-gamma power and event-related potential amplitude. However, other biomarkers including the auditory steady-state response, sleep spindles, and state-specific power spectral density were generally neurotypical. In conclusion, SRKO mice demonstrate how chronic NMDAR hypofunction contributes to deficits in certain translationally-relevant EEG biomarkers altered in schizophrenia. Importantly, our gamma band findings suggest an aberrant signal-to-noise ratio impairing cognition that occurs with NMDAR hypofunction, potentially tied to impaired task-dependent alteration in functional connectivity.

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“…Due to high sensitivity of inhibitory GABAergic neurons to NMDAR blockers (60,61), decreased expression of interneurons (62–64), and GABAergic markers (65–68), NMDAR hypofunction caused by reduced D-serine levels in schizophrenia may lead to disinhibition of excitatory neurons and result in glutamate spillover (69–72). Indeed, SRKO mice have been observed to have decreased PV expression and altered excitatory/inhibitory balance from GABAergic dysfunction (73–75). This disinhibition should result in greater release of glutamate at dendritic spines that, when paired with reduced D-serine levels, would increase the amount of non-ionotropic NMDAR activation even further to promote spine shrinkage (41) and decrease in spine density in the SRKO and schizophrenia (13, 14, 28).…”

Section: Discussionmentioning

confidence: 99%

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

Cited by 6 publications

References 146 publications

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

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

Altered neural oscillations and behavior in a genetic mouse 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

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