Work

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

Year: 2025

Type: article

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 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.

Source: Neurobiology of Disease

DOI: 10.1016/j.nbd.2025.106977

Authors: Hassan Hosseini, Sky Evans-Martin, Kevin S. Jones

Institutions: University of Michigan, Michigan Medicine

Language: English

Topic: Neuroscience and Neuropharmacology Research

Subfield: Cellular and Molecular Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,180