Abstract
Parvalbumin interneuron (PVI) activity synchronizes medial prefrontal cortex (mPFC) circuit for normal cognitive function and its impairment may contribute to schizophrenia (SZ). NMDA receptors in PVIs participate in these activities and form the basis for NMDA receptor hypofunction hypothesis of SZ. However, the role of GluN2D subunit, enriched in PVIs, in regulating molecular networks relevant to SZ is unknown.
Using electrophysiology and mouse model with conditional deletion of GluN2D from PVIs (PV-GluN2D KO) we examined the cell excitability and neurotransmission in mPFC. Histochemical, RNAseq analysis and immunoblotting were conducted to understand molecular mechanisms. Behavioral analysis was conducted to test cognitive function.
PVIs in mPFC were found to express putative GluN1/2B/2D receptors. In PV-GluN2D KO model PVIs were hypoexcitable whereas pyramidal neurons were hyperexcitable. Excitatory neurotransmission was higher in both cell types in PV-GluN2D KO whereas inhibitory neurotransmission showed contrasting changes which could be explained by reduced somatostatin interneuron projections and increased PVI projections. Genes associated with GABA synthesis, vesicular release, and uptake as well as those involved in formation of inhibitory synapses specifically GluD1-Cbln4 and Nlgn2 and regulation of dopamine terminals were downregulated in PV-GluN2D KO. SZ-susceptibility genes including Disc1, Nrg1 and ErbB4 and their downstream targets were also downregulated. Behaviorally PV-GluN2D KO mice showed hyperactivity and anxiety behavior and deficits in short-term memory and cognitive flexibility.
These findings demonstrate that GluN2D in PVIs serve as a point of convergence of pathways involved in the regulation of GABAergic synapses and relevant to SZ.