Principles of NMDA receptor co-agonism at cortical fast-spiking GABAergic interneurons in the adolescent prefrontal cortex
Abstract
N-methyl-D-aspartate receptors (NMDARs) populate fast-spiking (FS)-parvalbumin-positive (PV + ) GABAergic interneurons (INs), where they play a critical role in shaping circuit motifs and memory. However, it is largely unknown whether and how NMDARs at FS-PV + -INs are gated by their co-agonists and the functional relevance of such modulations for their synaptic coupling with excitatory neurons. Here, we report that FS-PV + -INs in the adolescent mouse prefrontal cortex, an area central to complex cognitive operation exhibit functional GluN2B/D containing NMDARs. These receptors contribute to the excitatory drive of FS-PV + -INs and to the feedforward inhibition, controlling short-term and long-term synaptic plasticity. While the identity of the co-agonist controlling GABAergic tone is tuned by the synaptic activity regime from d -serine to glycine, we reveal that it remains largely unchanged at the excitatory synapse with d -serine being the sole co-agonist gating NMDARs. Lastly, we show that d -serine-deficient mice, a model of NMDAR hypofunction show selective attenuation of PV + -INs excitation together with selective loss of temporal summation and long-term plasticity at the excitatory synapse. Our study reveals the segregation of pools of NMDARs at the soma and dendrites that are differently sensitive to D-serine or glycine, the existence of distinct modes of activity-dependent regulation of these NMDARs by their co-agonists at this major type of GABAergic INs, and hence the rules governing cortical inhibition by FS-PV + -INs during a critical period of late postnatal development. Significance Statement Our study sheds new light on brain circuit’s physiology by uncovering the general principles of NMDARs regulation at GABAergic interneurons by upstream signals released in their surrounding microenvironment. We discovered that d -serine but not glycine is critical for maintaining the activity of NMDARs at FS-PV + interneurons in the prelimbic area of the prefrontal cortex and that loss of its functions would recapitulate the synaptic deficits observed in several neuropsychiatric diseases like schizophrenia. These results could be exploited for the future development of more effective clinical interventions for treating NMDAR hypofunction by targeting inhibitory neurons.
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BibTeX
@misc{souza2026principles,
title = {{Principles of NMDA receptor co-agonism at cortical fast-spiking GABAergic interneurons in the adolescent prefrontal cortex}},
author = {Isis Souza and Pierre Lecouflet and Zeynep Okur and Steeve Maldera and Brigitte Potier and Loredano Pollegioni and Peter Scheiffele and Jean-Pierre Mothet},
howpublished = {HAL},
year = {2026},
month = aug,
doi = {10.64898/2026.08.30.747826},
url = {https://hal.science/hal-05791851v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - UNPB
TI - Principles of NMDA receptor co-agonism at cortical fast-spiking GABAergic interneurons in the adolescent prefrontal cortex
AU - Isis Souza
AU - Pierre Lecouflet
AU - Zeynep Okur
AU - Steeve Maldera
AU - Brigitte Potier
AU - Loredano Pollegioni
AU - Peter Scheiffele
AU - Jean-Pierre Mothet
PY - 2026
DA - 2026/08/30
PB - HAL
DO - 10.64898/2026.08.30.747826
UR - https://hal.science/hal-05791851v1
AB - N-methyl-D-aspartate receptors (NMDARs) populate fast-spiking (FS)-parvalbumin-positive (PV + ) GABAergic interneurons (INs), where they play a critical role in shaping circuit motifs and memory. However, it is largely unknown whether and how NMDARs at FS-PV + -INs are gated by their co-agonists and the functional relevance of such modulations for their synaptic coupling with excitatory neurons. Here, we report that FS-PV + -INs in the adolescent mouse prefrontal cortex, an area central to complex cognitive operation exhibit functional GluN2B/D containing NMDARs. These receptors contribute to the excitatory drive of FS-PV + -INs and to the feedforward inhibition, controlling short-term and long-term synaptic plasticity. While the identity of the co-agonist controlling GABAergic tone is tuned by the synaptic activity regime from d -serine to glycine, we reveal that it remains largely unchanged at the excitatory synapse with d -serine being the sole co-agonist gating NMDARs. Lastly, we show that d -serine-deficient mice, a model of NMDAR hypofunction show selective attenuation of PV + -INs excitation together with selective loss of temporal summation and long-term plasticity at the excitatory synapse. Our study reveals the segregation of pools of NMDARs at the soma and dendrites that are differently sensitive to D-serine or glycine, the existence of distinct modes of activity-dependent regulation of these NMDARs by their co-agonists at this major type of GABAergic INs, and hence the rules governing cortical inhibition by FS-PV + -INs during a critical period of late postnatal development. Significance Statement Our study sheds new light on brain circuit’s physiology by uncovering the general principles of NMDARs regulation at GABAergic interneurons by upstream signals released in their surrounding microenvironment. We discovered that d -serine but not glycine is critical for maintaining the activity of NMDARs at FS-PV + interneurons in the prelimbic area of the prefrontal cortex and that loss of its functions would recapitulate the synaptic deficits observed in several neuropsychiatric diseases like schizophrenia. These results could be exploited for the future development of more effective clinical interventions for treating NMDAR hypofunction by targeting inhibitory neurons.
ER -