Global Grin2a loss causes divergent impairments to PV+ and SST+ interneurons and alters gamma oscillations in prefrontal cortex

Abstract

Background

Loss-of-function mutations in the Grin2a gene, encoding the GluN2A subunit of NMDA receptors, confer elevated schizophrenia (SCZ) risk. Although GluN2A is expressed in multiple interneuron subtypes, its role in inhibitory circuit function remains incompletely understood. Recent genetic and transcriptomic studies implicate somatostatin-positive (SST⁺) interneurons in SCZ pathophysiology, raising the question of whether Grin2a deletion differentially affects SST⁺ and parvalbumin-positive (PV⁺) cells.

Methods

We utilized global Grin2a knockout (KO) and heterozygous (HET) mice to investigate how GluN2A deficiency affects inhibitory dynamics in the prelimbic (PrL) medial prefrontal cortex (mPFC). Immunohistochemistry quantified interneuron density, while slice electrophysiology and optogenetics assessed inhibitory postsynaptic current (IPSC) amplitude and kinetics, quantal GABA release, and PV⁺- and SST-driven gamma-band oscillations (GBOs).

Results

Grin2a KO and HET mice exhibited increased PV⁺ and SST⁺ interneuron density and a shift in excitatory–inhibitory (E/I) balance favoring inhibition. PV⁺ interneurons displayed functional impairments characterized by prolonged IPSC decay, elevated asynchronous GABA release, and enhanced PV-driven gamma-band oscillations (GBOs), consistent with impaired presynaptic calcium handling. In contrast, SST⁺ interneurons exhibited increased IPSC amplitudes without alterations in short-term plasticity or oscillatory drive, suggesting modulation of inhibitory tone without affecting network synchrony.

Conclusion

GluN2A loss appears to disrupt inhibitory networks through distinct cell-type-specific mechanisms—presynaptic dysfunction in PV⁺ cells and postsynaptic enhancement from SST⁺ cells. PV⁺ dysfunction aligns with gamma synchrony impairments linked to SCZ cognitive flexibility, while SST⁺ alterations may contribute to impaired feedback inhibition and sensory deficits. These findings clarify GluN2A's role in interneuron subtype function and network stability in SCZ.