IgSF21 promotes differentiation of inhibitory synapses via binding to neurexin2α

Abstract

Coordinated development of excitatory and inhibitory synapses is essential for higher brain function, and impairment in this development is associated with neuropsychiatric disorders. In contrast to the large body of accumulated evidence regarding excitatory synapse development, little is known about synaptic adhesion and organization mechanisms underlying inhibitory synapse development. Through unbiased expression screens and proteomics, we identified immunoglobulin superfamily member 21 (IgSF21) as a neurexin2α-interacting membrane protein that selectively induces inhibitory presynaptic differentiation. IgSF21 localizes postsynaptically and recruits axonal neurexin2α in a trans-interaction manner. Deleting IgSF21 in mice impairs inhibitory presynaptic organization, especially in the hippocampal CA1 stratum radiatum, and also diminishes GABA-mediated synaptic transmission in hippocampal CA1 neurons without affecting their excitatory synapses. Finally, mice lacking IgSF21 show a sensorimotor gating deficit. These findings suggest that IgSF21 selectively regulates inhibitory presynaptic differentiation through interacting with presynaptic neurexin2α and plays a crucial role in synaptic inhibition in the brain.

A Modular Organization of LRR Protein-Mediated Synaptic Adhesion Defines Synapse Identity

“…synapses (Tanabe et al, 2017). Ptprs KO mice show an increased mEPSC frequency in CA1 neurons (Horn et al, 2012), and expression of dominant-negative PTPs in zebrafish olfactory sensory neurons increases synaptic vesicle density and the number of docked vesicles (Chen et al, 2011), similar to the ultrastructural changes we observe following Slitrk1 KD.…”

IgSF9b regulates anxiety behaviors through effects on centromedial amygdala inhibitory synapses

“…Here we show that in the CeM, deletion of IgSF9b results in an enhancement of inhibitory synaptic transmission, likely through a presynaptic mechanism. In particular, the increases in mIPSC frequency and VIAAT staining without a concomitant increase in gephyrin indicate that IgSF9b deletion may result in an increase in the number of VIAAT-positive vesicles per synaptic terminal, analogous to effects recently observed in IgSF21 KO mice (albeit with opposite polarity) 41 . Together with the observation that IgSF9b, like its mammalian paralog IgSF9 and its Drosophila ortholog Turtle, forms primarily or exclusively homophilic interactions 14,16,42 , our data indicate that IgSF9b provides a transsynaptic signaling complex that regulates the organization of the inhibitory presynaptic terminal.…”

Choice of Alternative Polyadenylation Sites, Mediated by the RNA-Binding Protein Elavl3, Plays a Role in Differentiation of Inhibitory Neuronal Progenitors

“…Neurexins are presynaptic cell adhesion molecules implicated in various neuronal processes, including the differentiation, maturation, stabilization, and plasticity of both inhibitory and excitatory synapses (Bang and Owczarek, 2013). Recent data further indicate that neurexins are implicated in the differentiation of inhibitory synapses (Pettem et al, 2013; Tanabe et al, 2017), thus supporting a functional link between the alternative polyA+ site usage and neuronal differentiation.…”

“…Modulation of the Smad-repressor Pmepa1 (Liu et al, 2011), of Ppp2r1b (Yeh et al, 2007) and of Rbx1 (Carrano and Pagano, 2001) may contribute to inhibit cell cycle progression. Reduced expression of Serf2, previously identified as BE301622, induces neural stem cells differentiation (Wen et al, 2007), Znrf1 modulates axon extension (Yoshida et al, 2009) and presynaptic development (Araki and Milbrandt, 2003) while Nlgn1 and Cask are implicated in differentiation of inhibitory neurons and synapses (Pettem et al, 2013; Tanabe et al, 2017) by binding to neurexin family proteins (Bang and Owczarek, 2013). Importantly, mutations of Cask (Moog et al, 1993), Hrnrpu (Bramswig et al, 2017) and Gnb1 (Petrovski et al, 2016) genes have been associated to neurodevelopmental syndromes characterized by intellectual disability and epilepsy.…”