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

Abstract

Hypofunction 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 overexpressing NRG1 type I (NRG1tg-type-I mice). Immunohistochemical analyses confirmed that ErbB4 was coexpressed with either PV or CCK in hippocampal interneurons, but we observed a reduced number of ErbB4-immunopositive interneurons in the NRG1tg-type-I mice. NMDAR-mediated currents in interneurons expressing PV (including PV+ basket cells) or CCK were reduced in NRG1tg-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 NRG1tg-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.

Interneuron NMDA Receptor Ablation Induces Hippocampus-Prefrontal Cortex Functional Hypoconnectivity after Adolescence in a Mouse Model of Schizophrenia

“…For instance, Li et al (2007) reported that NRG2 stimulation of ErbB4 receptors results in NMDAR internalization in PV 1 interneurons but not in pyramidal cells. Another study has shown that overexpression of NRG1 Type I, an isoform of NRG1 that has elevated levels in some SZ patients, leads to reduced NMDAR synaptic activity in hippocampal PV 1 and CCK 1 interneurons (Kotzadimitriou et al, 2018), reinforcing the idea that, regardless of which NRG-ErBb4 component is affected in SZ, its impact on interneuron's physiology may converge on NMDAR. So, the combined evidence suggests that early postnatal dysfunction of PV 1 interneurons, arising directly by altered expression of the NMDAR, or indirectly by altered function of associated pathways, may be a key triggering pathophysiological factor for the altered neurodevelopment observed in SZ.…”

Dendritic NMDA receptors in parvalbumin neurons enable strong and stable neuronal assemblies

“…When coupled with the observation that NMDAR antagonists cause a net disinhibition of principal cell activity (Homayoun and Moghaddam, 2007;Jackson et al, 2004), it has been suggested that cortical circuits are especially vulnerable to failure of NMDARmediated signalling in PV+ interneurons. Moreover, post-mortem studies have revealed a selective loss of PV+ interneurons in people with schizophrenia (Lewis et al, 2012) and overexpression of Neuregulin 1, a leading schizophrenia susceptibility gene, is associated with a reduction of NMDARs on PV+ cells (Kotzadimitriou et al, 2018). Destabilisation of dominant neuronal assemblies, as shown here to result from impaired NMDAR signalling on PV+ interneurons, may thus explain a failure of sensory gating (Javitt and Freedman, 2015) and evidence for reduced cognitive control, for instance in the Necker cube test (McBain et al, 2011), in schizophrenia.…”

“…Moreover, impaired NMDAR-mediated signalling in PV+ interneurons has been suggested to be a core feature of schizophrenia (Coyle, 2012;Lisman et al, 2008). Indeed, genetic manipulation of the schizophrenia risk genes encoding neuregulin and ErbB4, which amongst other functions regulate NMDARs, impairs recruitment of PV+ interneurons and recapitulates some features of the disease (delPino et al, 2013;Kotzadimitriou et al, 2018).…”

Robust perisomatic GABAergic self-innervation inhibits basket cells in the human and mouse supragranular neocortex

“…Pv+ cells in mouse brain slices. Transversal slices (350 μm) from somatosensory cortex were prepared (Kotzadimitriou D et al 2018) from 4-to 6-week-old heterozygous male CB6-Tg(Gad1-EGFP)G42Zjh/J -mice (The Jackson Laboratory, stock 007677, GAD67-GFP G42 line) expressing td-Tomato fluorophore preferably in parvalbumin GABAergic neurons (Chattopadhyaya B et al 2004). Cells were confirmed to be fast-spiking, showing fast spike kinetics and a high-frequency non-accommodation firing pattern for suprathreshold depolarizing 500 ms pulses ( Supplementary Table 1).…”