Schizophrenia-relevant behaviours of female mice overexpressing neuregulin 1 type III

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Abstract

Elevated levels of the type III (III) isoforms of neuregulin 1 (NRG1) have been observed in the brains of schizophrenia patients that carry NRG1 HapICE risk alleles, which is thought to contribute to the aetiology of the disease. We generated transgenic mice with forebrain driven Nrg1 III overexpression (Nrg1 III tg) and previously found that male heterozygous Nrg1 type III tg mice exhibit several schizophrenia-relevant behaviours including social and cognitive deficits as well as impaired sensorimotor gating. A number of mouse models for other Nrg1 isoform types exhibit sex-specific phenotypes yet sex-specific effects of Nrg1 III overexpression had not been evaluated. Thus, in this study we tested female Nrg1 III transgenic mice using a comprehensive behavioural phenotyping battery relevant to positive, negative and cognitive symptoms of schizophrenia. Firstly, forebrain Nrg1 III mRNA overexpression was confirmed in female transgenic mice using by qPCR. In the open field test, female Nrg1 III mice exhibited a blunted response to an acute challenge with the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801. Female Nrg1 III tg mice also exhibited moderately impaired short-term memory. Other behavioural domains including sensory abilities, motor functions, baseline locomotion, anxiety, sociability, social recognition memory, fear conditioning and prepulse inhibition were unperturbed in Nrg1 III tg females. Together these results illustrate that overexpressing forebrain Nrg1 III in female mice modifies the locomotive response to NMDA receptor antagonism without causing severe alterations to a number of other schizophrenia-related behavioural domains. The data suggest that behavioural effects of Nrg1 III overexpression may be sex-dependent.

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