Sex-specific neuroendocrine and behavioral phenotypes in hypomorphic Type II Neuregulin 1 rats

Neuregulin 1 (NRG1) is an important growth factor involved in the development and plasticity of the central nervous system. Since its identification as a susceptibility gene for schizophrenia, several transgenic mouse models have been employed to elucidate the role NRG1 may play in the pathogenesis of psychiatric disease. Unfortunately very few studies have included females, despite the fact that some work suggests that the consequences of disrupted NRG1 expression may be sex-specific. Here, we used Nrg1 hypomorphic (Nrg1Tn) Fischer rats to demonstrate sex-specific changes in neuroendocrine and behavioral phenotypes as a consequence of reduced Type II NRG1 expression. We have previously shown that male Nrg1Tn rats have increased basal corticosterone levels, and fail to habituate to an open field despite normal overall levels of locomotor activity. The current studies show that, in contrast, female Nrg1Tn rats exhibit enhanced suppression of corticosterone levels following an acute stress, reduced locomotor activity, and enhanced habituation to novel environments. Furthermore, we also show that female, but not male, Nrg1Tn rats have impaired prepulse inhibition. Finally, we provide evidence that sex-specific changes are not likely attributable to major disruptions in the hypothalamic-pituitary-gonadal axis, as measures of pubertal onset, estrous cyclicity, and reproductive capacity were unaltered in female Nrg1Tn rats. Our results provide further support for both the involvement of NRG1 in the control of hypothalamic-pituitary-adrenal axis function and the sex-specific nature of this relationship.

► Female Nrg1Tn rats exhibit normal pubertal onset and reproductive capability. ► Female Nrg1Tn rats exhibit enhanced neuroendocrine recovery after acute stress. ► Unlike male Nrg1Tn rats, females show enhanced habituation to novel environments. ► Female Nrg1Tn rats display reduced locomotion and PPI, whereas males do not ► Disruption of Type II NRG1 results in sex-specific phenotypes.