Distinct phenotypes of new transmembrane-domain neuregulin 1 mutant mice and the rescue effects of valproate on the observed schizophrenia-related cognitive deficits

Abstract

Accumulating evidence suggests that neuregulin 1 (NRG1) might be involved in the neurodevelopment, neural plasticity, GABAergic neurotransmission, and pathogenesis of schizophrenia. NRG1 is abundantly expressed in the hippocampus, and emerging studies have begun to reveal the link between NRG1 signaling and cognitive deficits in schizophrenic patients. Because the transmembrane domain of NRG1 is vital for both forward and reverse signaling cascades, new Nrg1-deficient mice that carry a truncation of the transmembrane domain of the Nrg1 gene were characterized and used in this study to test a NRG1 loss-of-function hypothesis for schizophrenia. Both male and female Nrg1 heterozygous mutant mice and their wild-type littermates were used in a series of 4 experiments to characterize the impact of Nrg1 on behavioral phenotypes and to determine the importance of Nrg1 in the regulation of hippocampal neuromorphology and local GABAergic interneurons. First, a comprehensive battery of behavioral tasks indicated that male Nrg1-deficient mice exhibited significant impairments in cognitive functions. Second, pharmacological challenges were conducted and revealed that Nrg1 haploinsufficiency altered GABAergic activity in males. Third, although no genotype-specific neuromorphological alterations were found in the hippocampal CA1 pyramidal neurons, significant reductions in the hippocampal expressions of GAD67 and parvalbumin were revealed in the Nrg1-deficient males. Fourth, chronic treatment with valproate rescued the observed behavioral deficits and hippocampal GAD67 reduction in Nrg1-deficient males. Collectively, these results indicate the potential therapeutic effect of valproate and the importance of Nrg1 in the regulation of cognitive functions and hippocampal GABAergic interneurons, especially in males.

Neuregulin-1 and schizophrenia in the genome-wide association study era

“…Guidotti et al 2000;Hashimoto et al 2003) and other transcriptional markers of GABA, such as mRNA expression of the 1, 5 and  subunits of the GABA A receptor in the brain of patients with schizophrenia. In agreement with this human postmortem finding, a study by (Pei et al 2014) found abnormally low levels of GAD67 in male, but not female, type I Nrg1 "knockout" mice in the hippocampus, and another study by (Yin et al 2013) observed elevated 1 in type I Nrg1 overexpressing mice relative to wild type mice in frontal cortex and hippocampus. In light of the human postmortem findings, it may be that Nrg1 leads to small and often undetectable changes in GAD67 and other markers of GABAergic activity through its selective more potent effects on PV+ interneurons, but it is only when combined with the effects of several other risk genes and environmental stressors in patients with schizophrenia, that broader aberrations in GABA occur.…”

“…For example, levels of parvalbumin are elevated in the frontal cortex in type I Nrg1 overexpressing mice compared to wild type mice . In contrast, the TM Nrg1 model is associated with reduced parvalbumin in the hippocampus for male, but not female, mice (Pei et al 2014). Also, genetic ablation of the Nrg1 receptor tyrosine kinase, ErbB4, down-regulates the number of PV + interneurons in the same brain region by 30% from normal levels (Fisahn et al 2009).…”

Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology

“…Male-specific deficits in object recognition were confirmed by Pei et al, however this group found that cue-dependent fear conditioning was also impaired in males but not females (Pei et al 2014). Furthermore, male but not female TM-Nrg1 +/-show reduced hippocampal protein expression of the GABA synthesizing enzyme GAD67 and the fast-spiking GABAergic interneuron marker, parvalbumin (Pei et al 2014). These fastspiking interneurons are thought to be critically involved in the regulation of cognitive function (Uhlhaas 2013).…”

Translating advances in the molecular basis of schizophrenia into novel cognitive treatment strategies

“…Neonatal, peripheral administration of NRG1 type 1 protein in mice has also been shown to produce adult deficits in sensorimotor gating and learned inattention tasks, and these were reversed by antipsychotic treatment during adulthood (Kato et al, ). A novel line of transmembrane‐domain partial Nrg1 deletion showed a sex‐specific (males only) deficit in object recognition memory, as well as in both contextual and cued fear learning (Pei et al, ); these cognitive deficits were reversed by chronic treatment with valproate, a mood stabilizer and anticonvulsant with actions that include potentiation of GABAergic function.…”