Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCA287

Poster Communications

Lack of CIN85 in the brain causes impairment of maternal behaviour in mice

N. Shimokawa1,2, T. J. Sairenji2, S. Masuda2, N. Koibuchi2

1. Department of Nutrition, Takasaki University of Health and Welfare, Takasaki, Gunma, Japan. 2. Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Cbl-interacting protein of 85 kDa (CIN85) is a multi-adaptor protein implicated in the regulation of receptor endocytosis, cell division and the cellular cytoskeleton (Haglund et al., 2002). To investigate the function of CIN85 in the central nervous system, we generated mice deficient of the two major CIN85 isoforms expressed in the brain (CIN85Δex2 mice). Mice deficient of brain-specific CIN85 expression show hyperactive phenotypes. As a molecular explanation of this phenotype, we concluded that the absence of striatal CIN85 causes insufficient complex formation of endophilins with dopamine receptors in the striatum and ultimately decreased dopamine receptor endocytosis in striatal neurons in response to dopamine stimulation (Shimokawa et al., 2010). Here we show another phenotype of CIN85Δex2 mice; that of maternal neglect of the newborn pups, and demonstrate that CIN85 contributes to expression of maternal behavior in the next generation through dopamine-prolactin signaling. Even though there is no difference in the number of live births from CIN85Δex2 homozygote and wild-type mothers, almost all pups born to CIN85Δex2 homozygote mothers have died within two days of birth. This could be explained by the fact that CIN85Δex2 mothers showed significantly decreased arched-back nursing, a kind of maternal behavior and pups from CIN85Δex2 mothers were often found scattered within the bedding. Moreover, despite of the fact that no defect in the mammary glands of CIN85Δex2 mother mice was found, milk was not detected in the stomachs of most pups. Importantly, when measuring the plasma levels of prolactin, we detected significantly decreased prolactin levels in CIN85Δex2 mice compared to heterozygote and wild-type mice. Prolactin injection in CIN85Δex2 mice during pregnancy (0.07 μg/g body weight, s.c., twice a day) could however partially rescue the defect in maternal behavior of the next generation. Taken together, the low nursing ability by CIN85Δex2 mothers of their newborn pups may partially be due to the lack of exposure to prolactin during their fetal period. Our findings indicate an important role of CIN85 in the regulation of the dopamine-prolactin system in the brain and provide new insight into a molecular explanation for maternal behavior.

Where applicable, experiments conform with Society ethical requirements