Abstract
Extensive evidence suggests a dysfunction of the glutamate NMDA receptor (NMDAR) in schizophrenia, a severe psychiatric disorder with putative early neurodevelopmental origins, but clinical onset mainly during late adolescence. On the other hand, pharmacological models using NMDAR antagonists and the clinical manifestation of anti-NMDAR encephalitis indicate that NMDAR blockade/hypofunction can trigger psychosis also at adult stages, without any early developmental dysfunction. Previous genetic models of NMDAR hypofunction restricted to parvalbumin-positive interneurons indicate the necessity of an early postnatal impairment to trigger schizophrenia-like abnormalities, whereas the cellular substrates of NMDAR-mediated psychosis at adolescent/adult stages are unknown. Neuregulin 1 (NRG1) and its receptor ErbB4 represent schizophrenia-associated susceptibility factors that closely interact with NMDAR. To determine the neuronal populations implicated in “late” NMDAR-driven psychosis, we analyzed the effect of the inducible ablation of NMDARs in ErbB4-expressing cells in mice during late adolescence using a pharmacogenetic approach. Interestingly, the tamoxifen-inducible NMDAR deletion during this late developmental stage did not induce behavioral alterations resembling depression, schizophrenia or anxiety. Our data indicate that post-adolescent NMDAR deletion, even in a wider cell population than parvalbumin-positive interneurons, is also not sufficient to generate behavioral abnormalities resembling psychiatric disorders. Other neuronal substrates that have to be revealed by future studies, may underlie post-adolescent NMDAR-driven psychosis.
Highlights
Despite intense research, the molecular and cellular mechanisms of psychotic disorders, like schizophrenia and anti-NMDA receptor (NMDAR) encephalitis that emerge often during post-adolescence/young adulthood, are only partly understood
Our study provides the first characterization of a genetic model of inducible genetic ablation of NMDAR during late adolescence in neurons expressing the Neuregulin 1 (NRG1) receptor ErbB4, with relevance for psychiatric disorders, considering that NRG1 and ErbB4 are main candidate risk genes gene for schizophrenia [26]
The present results appear at a first glance surprising since mutant mice heterozygous for either NRG1 or ErbB4 show a behavioral phenotype that resembles alterations seen in schizophrenia and, NRG1 hypomorphs, expressing 50% of the normal levels of NRG1, have 16% fewer functional NMDARs than wild-type mice [26]
Summary
The molecular and cellular mechanisms of psychotic disorders, like schizophrenia and anti-NMDA receptor (NMDAR) encephalitis that emerge often during post-adolescence/young adulthood, are only partly understood. Proteins structurally and functionally closely linked to NMDAR, like NRG1 display strong positive genetic association with schizophrenia [10], whereas abnormal cortical oscillations triggered by NMDAR dysfunction [11] represent an electrophysiological endophenotype of schizophrenia [12]. Mice with reduced NMDAR expression (GluN1/Grin knockdown, KD) that express 5–10% of the normal NMDAR levels, are viable and display schizophrenia-like abnormalities [19]. This global NMDAR KD model does not allow the identification of the neuronal populations implicated in psychosis. Abnormal synchronization of gamma-band activity may underlie cognitive deficits in schizophrenia [22]
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