Cognitive Deficits in Calsyntenin-2-deficient Mice Associated with Reduced GABAergic Transmission

Abstract

Calsyntenin-2 has an evolutionarily conserved role in cognition. In a human genome-wide screen, the CLSTN2 locus was associated with verbal episodic memory, and expression of human calsyntenin-2 rescues the associative learning defect in orthologous Caenorhabditis elegans mutants. Other calsyntenins promote synapse development, calsyntenin-1 selectively of excitatory synapses and calsyntenin-3 of excitatory and inhibitory synapses. We found that targeted deletion of calsyntenin-2 in mice results in a selective reduction in functional inhibitory synapses. Reduced inhibitory transmission was associated with a selective reduction of parvalbumin interneurons in hippocampus and cortex. Clstn2(-/-) mice showed normal behavior in elevated plus maze, forced swim test, and novel object recognition assays. However, Clstn2(-/-) mice were hyperactive in the open field and showed deficits in spatial learning and memory in the Morris water maze and Barnes maze. These results confirm a function for calsyntenin-2 in cognitive performance and indicate an underlying mechanism that involves parvalbumin interneurons and aberrant inhibitory transmission.

Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

“…Second, calsyntenins were shown to bind to neurexins with an affinity that is only slightly lower than that of neurexins, and proposed to function as postsynaptic cell-adhesion molecules (Pettem et al, 2013; Um et al, 2014; Lu et al, 2014). In support of this hypothesis, calsyntenin is synaptogenic in the artificial synapse formation assay (Pettem et al, 2013; Um et al, 2014), and calsyntenin knockouts exhibit synaptic phenotypes, albeit very modest ones (Pettem et al, 2013; Ster et al, 2014; Lipina et al, 2016). Although at present these two disparate strings of experiments appear incompatible, it is possible that they can be reconciled, i.e.…”

Molecular Diversity of Intrinsically Photosensitive Ganglion Cells

“…Another semaphorin, Sema5a , was also significantly enriched in developing ipRGCs. Other differentially expressed cell-adhesion molecules Salm5 ( Lrfn5 ), Clstn2, Thbs1, Lrrtm2, Pcdh19, Ptprm , and Lrrc4c (Ngl1) could play significant roles in the formation of ipRGC synapses (Burden-Gulley and Brady-Kalnay, 1999; Lin et al, 2003; de Wit et al, 2009; Xu et al, 2010; Lipina et al, 2016; Pederick et al, 2016; Lin et al, 2018). The cell surface glycoprotein Mdga1 was also differentially expressed in developing ipRGCs, and is known to influence the formation and maintenance of inhibitory synapses (Pettem et al, 2013).…”

Positive and balancing selection onSLC18A1gene associated with psychiatric disorders and human-unique personality traits

“…Although there have been no reports on the effects of the human-specific amino acid substitutions in the other two genes, CLSTN2, which encodes calsyntenin 2, and FAT1, which encodes FAT atypical cadherin 1, both belong to the cadherin super family (Gul et al 2017) and have been surveyed for their roles in neural function. CLSTN2 is predominantly expressed in the brain (Hintsch 2002) and is involved in learning and memory (Jacobsen et al 2009;Preuschhof et al 2010;Lipina et al 2016), and its function is evolutionarily conserved even in Caenorhabditis elegans (Ikeda et al 2008;Hoerndli et al 2009). FAT1 is involved in cellcell contacts and lamellipodial dynamics (Ciani et al 2003), and Fat1-deficient mice exhibits defects in forebrain and eye development (Tanoue and Takeichi 2004).…”