Loss of calsyntenin paralogs disrupts interneuron stability and mouse behavior

Abstract

Calsyntenins (CLSTNs) are important synaptic molecules whose molecular functions are not fully understood. Although mutations in calsyntenin (CLSTN) genes have been associated with psychiatric disorders in humans, their function is still unclear. One of the reasons why the function of CLSTNs in the nervous system has not been clarified is the functional redundancy among the three paralogs. Therefore, to investigate the functions of mammalian CLSTNs, we generated triple knockout (TKO) mice lacking all CLSTN paralogs and examined their behavior. The mutant mice tended to freeze in novel environments and exhibited hypersensitivity to stress. Consistent with this, glucose levels under stress were significantly higher in the mutant mice than in the wild-type controls. In particular, phenotypes such as decreased motivation, which had not been reported in single Clstn KO mice, were newly discovered. The TKO mice generated in this study represent an important mouse model for clarifying the function of CLSTN in the future.

Genome-wide identification and spatiotemporal expression analysis of cadherin superfamily members in echinoderms

“…Calsyntenins (CSTNs) are atypical cadherins that are essential for regulating the secretion of the inhibitory neurotransmitter, GABA, within protostome and deuterostome synapses (Fig. 1 ) [ 46 – 48 ]. Loss-of-function mutations in CSTN1 have been shown to reduce GABAergic neurotransmission within mice interneuron populations [ 46 , 47 ] and at neuromuscular junctions in C. elegans [ 48 ].…”

“…1 ) [ 46 – 48 ]. Loss-of-function mutations in CSTN1 have been shown to reduce GABAergic neurotransmission within mice interneuron populations [ 46 , 47 ] and at neuromuscular junctions in C. elegans [ 48 ]. Because of their impacts on neuronal communication, mutations in genes encoding protocadherins and CSTNs are associated with multiple human neurodevelopmental disorders [ 44 , 47 ].…”