AUTS2 Governs Cerebellar Development, Purkinje Cell Maturation, Motor Function and Social Communication.

Kunihiko Yamashiro,Esther S.K Lai,Nariko Arimura,Saki F Egusa,Masanobu Kano,Takaki Watanabe,Naofumi Uesaka,Asami Sakamoto,Ryo Aoki,Kenji Sakimura,Manabu Abe,Kei Hori,Kazumi Shimaoka,Mikio Hoshino

doi:10.1016/j.isci.2020.101820

Abstract

SummaryAutism susceptibility candidate 2 (AUTS2), a risk gene for autism spectrum disorders (ASDs), is implicated in telencephalon development. Because AUTS2 is also expressed in the cerebellum where defects have been linked to ASDs, we investigated AUTS2 functions in the cerebellum. AUTS2 is specifically localized in Purkinje cells (PCs) and Golgi cells during postnatal development. Auts2 conditional knockout (cKO) mice exhibited smaller and deformed cerebella containing immature-shaped PCs with reduced expression of Cacna1a. Auts2 cKO and knock-down experiments implicated AUTS2 participation in elimination and translocation of climbing fiber synapses and restriction of parallel fiber synapse numbers. Auts2 cKO mice exhibited behavioral impairments in motor learning and vocal communications. Because Cacna1a is known to regulate synapse development in PCs, it suggests that AUTS2 is required for PC maturation to elicit normal development of PC synapses and thus the impairment of AUTS2 may cause cerebellar dysfunction related to psychiatric illnesses such as ASDs.

Highlights

The cerebellum is a well-defined brain region known to control motor coordination and function
Because Autism susceptibility candidate 2 (AUTS2) is expressed in the cerebellum where defects have been linked to autism spectrum disorders (ASDs), we investigated AUTS2 functions in the cerebellum
Because Cacna1a is known to regulate synapse development in Purkinje cells (PCs), it suggests that AUTS2 is required for PC maturation to elicit normal development of PC synapses and the impairment of AUTS2 may cause cerebellar dysfunction related to psychiatric illnesses such as ASDs

Summary

Introduction

The cerebellum is a well-defined brain region known to control motor coordination and function. Because its highly stereotyped cytoarchitecture is composed of fewer types of neuronal cells compared with other brain regions, the cerebellum has been used as a good model system to study neurogenesis and cell morphogenesis as well as circuit assembly (Sillitoe and Joyner, 2007). Among neurons in the cerebellar cortex, Purkinje cells (PCs) are the sole output neurons that extend a long axon to deep cerebellar nuclei (DCN) neurons (White and Sillitoe, 2013). Functional magnetic resonance imaging (fMRI) studies on human subjects have revealed that the activation of the cerebellum is associated with social cognition and emotional processing (Schmahmann and Caplan, 2006; Van Overwalle et al, 2014). Animal models of various neurological disorders revealed that a reduction in the number or dysfunction of PCs leads to abnormal social behaviors (Tsai et al, 2012). Despite the significance of proper development and function of PCs for socio-cognitive processes in the cerebellum, the pathological mechanisms underlying how impairments of development or function of PCs contribute to neurological disorders remain to be clarified

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