Metabotropic glutamate receptor subtype 7 has critical roles in regulation of the endocrine system and social behaviours

Abstract

Metabotropic glutamate receptor subtype 7 (mGluR7) is one of the group III mGluRs, which are negatively coupled to adenylate cyclase via Gi/Go proteins and localised to presynaptic active zones of the mammalian central nervous system. We previously reported that mGluR7 is essential for intermale aggression and amygdala-dependent fear learning. To elucidate the role of mGluR7 in the neuroendocrine system, we performed biochemical analyses and found a significant reduction of testosterone levels in mGluR7 knockout (KO) mice. Testosterone replacement restored intermale aggressive behaviour in castrated wild-type mice to the level of gonadally intact wild-type mice. However, given the same dosage of testosterone replacement, mGluR7 KO mice showed almost no aggressive behaviour. These results indicate that reduction of plasma testosterone is unrelated to the deficit in intermale aggression in mGluR7 KO mice. Social investigating behaviour of intact mGluR7 KO mice also differed from that of wild-type mice; e.g. the KO mice showing less frequent anogenital sniffing and more frequent grooming behaviour. Testosterone replacement increased anogenital sniffing and grooming behaviour in castrated mGluR7 KO mice, while the differences were still present between castrated wild-type mice and KO mice after both underwent testosterone replacement. These results imply that reduction of plasma testosterone may partially inhibit social investigating behaviours in intact mGluR7 KO mice. Furthermore, castrated mGluR7 KO mice have smaller seminal vesicles than those of castrated wild-type mice, although seminal vesicle weights were normal in intact mice. These observations suggest that, besides testicular testosterone, some other hormone levels may be dysregulated in mGluR7 KO mice, and indicate a critical role of mGluR7 in the endocrine system. Taken together, our findings demonstrate that mGluR7 is essential for the regulation of the endocrine system, in addition to innate behaviours such as intermale aggression and fear response.

Phenotypic profiling of mGlu7 knockout mice reveals new implications for neurodevelopmental disorders

“…Masugi-Tokita et al recently showed that mGlu 7 in the bed nucleus of the stria terminalis is essential for intermale aggression, and that male Grm7 −/− mice show less frequent anogenital sniffing and more frequent grooming of an intruder. 32,33 In female mice, Gryksa et al showed that Grm7 −/− animals exhibit decreased maternal aggression and increased maternal care. 34 Additionally, the mGlu 7 negative allosteric modulator (NAM) MMPIP was reported to decrease social interaction time in rats.…”

Mating with immunised male mice affects the phenotype of adult progeny

“…For example, the predominance of excitatory (glutamate/glutamine) neurotransmitters over inhibitory (GABA, alanine) ones in the amygdala may be a factor that contributes to the higher level of androgens in the offspring of immunised fathers. Indeed, mice with a knockout of the metabotropic glutamate receptor subtype 7 gene are characterised by a lower blood testosterone level compared with wild-type mice (Masugi-Tokita et al 2018). Likewise, prenatal testosterone affects the development of the amygdala, which has been shown in both experimental and clinical studies (Kerchner et al 1995, Lombardo et al 2012.…”