Neuregulin 1 Type I Overexpression Is Associated with Reduced NMDA Receptor–Mediated Synaptic Signaling in Hippocampal Interneurons Expressing PV or CCK

Abstract

WHypofunction of N-methyl-d-aspartate receptors (NMDARs) in inhibitory GABAergic interneurons is implicated in the pathophysiology of schizophrenia (SZ), a heritable disorder with many susceptibility genes. However, it is still unclear how SZ risk genes interfere with NMDAR-mediated synaptic transmission in diverse inhibitory interneuron populations. One putative risk gene is neuregulin 1 (NRG1), which signals via the receptor tyrosine kinase ErbB4, itself a schizophrenia risk gene. The type-I isoform of NRG1 shows increased expression in the brain of SZ patients, and ErbB4 is enriched in GABAergic interneurons expressing parvalbumin (PV+) or cholecystokinin (CCK+). Here, we investigated ErbB4 expression and synaptic transmission in interneuronal populations of the hippocampus of transgenic mice over-expressing NRG1 type-I (NRG1^tg-type-I mice). Immunohistochemical analyses confirmed that ErbB4 was co-expressed with either PV or CCK in hippocampal interneurons, but we observed a reduced number of ErbB4-immunopositive interneurons in the NRG1^tg-type-I mice. NMDAR-mediated currents in interneurons expressing PV (including PV+ basket cells) or CCK were reduced in NRG1^tg-type-I mice compared to their littermate controls. We found no difference in AMPA receptor-mediated currents. Optogenetic activation (5 pulses at 20 Hz) of local glutamatergic fibers revealed a decreased NMDAR-mediated contribution to disynaptic GABAergic inhibition of pyramidal cells in the NRG1^tg-type-I mice. GABAergic synaptic transmission from either PV+ or CCK+ interneurons, and glutamatergic transmission onto pyramidal cells, did not significantly differ between genotypes. The results indicate that synaptic NMDAR-mediated signaling in hippocampal interneurons is sensitive to chronically elevated NGR1 type-I levels. This may contribute to the pathophysiological consequences of increased NRG1 expression in SZ. Significance Statement Hypofunction of NMDA receptors in inhibitory GABAergic interneurons is implicated in pathophysiology of schizophrenia (SZ), but it is largely unknown how SZ risk genes interfere with NMDAR-mediated signaling in specific interneurons. We investigated synaptic transmission in hippocampus of mice over-expressing the type-I isoform of the putative SZ risk gene, NRG1, and found markedly reduced NMDAR-mediated synaptic responses in GABAergic interneuron types labeled for PV or CCK which are known to express the NRG1 receptor ErbB4. The NMDAR hypofunction changed synaptic excitatory drive of interneurons during hippocampal network activity. The observed reductions of NMDAR-mediated transmission in these interneurons may contribute to the hippocampal dysfunction observed with increased NGR1 type-I expression, and may provide a link to the genetic predisposition to SZ.