Abstract
Although there is considerable genetic and pathologic evidence for an association between neuregulin 1 (NRG1) dysregulation and schizophrenia, the underlying molecular and cellular mechanisms remain unclear. Mutant mice containing disruption of the transmembrane (TM) domain of the NRG1 gene constitute a heuristic model for dysregulation of NRG1-ErbB4 signaling in schizophrenia. The present study focused on hitherto uncharacterized information processing phenotypes in this mutant line. Using a mass spectrometry-based metabolomics approach, we also quantified levels of unique metabolites in brain. Across 2 different sites and protocols, Nrg1 mutants demonstrated deficits in prepulse inhibition, a measure of sensorimotor gating, that is, disrupted in schizophrenia; these deficits were partially reversed by acute treatment with second, but not first-, generation antipsychotic drugs. However, Nrg1 mutants did not show a specific deficit in latent inhibition, a measure of selective attention that is also disrupted in schizophrenia. In contrast, in a “what–where–when” object recognition memory task, Nrg1 mutants displayed sex-specific (males only) disruption of “what–when” performance, indicative of impaired temporal aspects of episodic memory. Differential metabolomic profiling revealed that these behavioral phenotypes were accompanied, most prominently, by alterations in lipid metabolism pathways. This study is the first to associate these novel physiological mechanisms, previously independently identified as being abnormal in schizophrenia, with disruption of NRG1 function. These data suggest novel mechanisms by which compromised neuregulin function from birth might lead to schizophrenia-relevant behavioral changes in adulthood.
Highlights
2 cohorts of TM-domain Nrg[1] mutants were used, each tested at different phenotyping facilities. Both groups of experimental animals were bred and weaned at the Biomedical Research Facility at Royal College of Surgeons in Ireland (RCSI), Dublin: mice used in the latent inhibition (LI), Prepulse inhibition (PPI), and episodic memory studies were shipped to the housing facility at the University of Nottingham at 7–10 weeks of age, with testing commencing 3 weeks after arrival; mice used in the PPI study with drug treatment were tested at RCSI, Dublin
LI was assessed using a conditioned lick suppression paradigm, where intact LI comprises reduced learning of a conditioned stimulus (CS)–unconditioned stimulus (US) association in a group pre-exposed to that stimulus without reinforcement compared with a group without such preexposure.[45]
LI is a paradigm with high construct validity to model the disrupted attentional salience processes of schizophrenia, and has received robust validation as a pharmacological and genetic model of processes related to schizophrenia.[20]
Summary
Neuregulin-1 (NRG1) is a gene that has been associated with increased risk for schizophrenia across diverse populations.[1,2,3] Studies on postmortem brain and serum from schizophrenia cases have reported up-regulation of specific NRG1/ErbB4 splice variants and increased NRG1 signaling,[4,5,6,7,8,9] and decreased isoform-specific expression of NRG1 transcripts.[9,10] despite such combined genetic and pathologic evidence for NRG1 dysregulation in schizophrenia, the mechanisms underlying this association remain unclear.[11]. Multiple NRG1 isoforms have been described, the diversity of which is due to alternative splicing and the existence of multiple 5′ flanking regulatory elements. Altered NRG1 expression has been identified in several schizophrenia-relevant rodent models,[15,16,17] and several Nrg[1] knockout/transgenic mouse lines have been developed to study the impact of altered NRG1 signaling on endophenotypes relevant to schizophrenia.[18,19] The most well-characterized Nrg[1] mutant model involves heterozygous deletion of the
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