GABA Neuronal Deletion of Shank3 Exons 14-16 in Mice Suppresses Striatal Excitatory Synaptic Input and Induces Social and Locomotor Abnormalities.

Taesun Yoo,Ye-Eun Yoo,Eunjoon Kim,Haram Park,Hyun Kim,Heejin Cho,Jin Yong Kim,Esther Yang,Jiseok Lee

doi:10.3389/fncel.2018.00341

Abstract

Shank3 is an excitatory postsynaptic scaffolding protein implicated in multiple brain disorders, including autism spectrum disorders (ASD) and Phelan-McDermid syndrome (PMS). Although previous neurobiological studies on Shank3 and Shank3-mutant mice have revealed diverse roles of Shank3 in the regulation of synaptic, neuronal and brain functions, whether Shank3 expression in specific cell types distinctly contributes to mouse phenotypes remains largely unclear. In the present study, we generated two Shank3-mutant mouse lines (exons 14–16) carrying global and GABA neuron-specific deletions and characterized their electrophysiological and behavioral phenotypes. These mouse lines show similar decreases in excitatory synaptic input onto dorsolateral striatal neurons. In addition, the abnormal social and locomotor behaviors observed in global Shank3-mutant mice are strongly mimicked by GABA neuron-specific Shank3-mutant mice, whereas the repetitive and anxiety-like behaviors are only partially mimicked. These results suggest that GABAergic Shank3 (exons 14–16) deletion has strong influences on striatal excitatory synaptic transmission and social and locomotor behaviors in mice.

Highlights

These results suggest that Shank3 mRNA is expressed in both glutamatergic and GABAergic neurons
The electrophysiological and behavioral phenotypes observed in global Shank3∆14–16 mice are strongly mimicked by ViaatCre;Shank3∆14–16 mice, the repetitive and anxiety-like behavioral deficits in global Shank3∆14–16 mice are partially mimicked by Viaat-Cre;Shank3∆14–16 mice. The result that both the frequency and amplitude of mEPSCs are reduced in global Shank3∆14–16 mice (Figure 3) further strengthens the notion that Shank3 is important for the development and function of excitatory synapses in the dorsal striatum
Similar decreases in the frequency and amplitude of mEPSCs in the dorsal striatum have been observed in the Shank3 mouse line lacking exons 13–16 (Shank3B−/− mice; Peca et al, 2011; Mei et al, 2016; Wang et al, 2017)

Summary

Introduction

Shank represents a family of postsynaptic scaffolding proteins with three known members: Shank1/ProSAP3, Shank2/ProSAP1 and Shank3/ProSAP2 (Sheng and Kim, 2000; Sheng and Sala, 2001; Boeckers et al, 2002; Sheng and Hoogenraad, 2007; Grabrucker et al, 2011; Sheng and Kim, 2011; Jiang and Ehlers, 2013; Sala et al, 2015; Monteiro and Feng, 2017; Mossa et al, 2017). Mutations of SHANK3 (Boeckers et al, 1999; Lim et al, 1999; Naisbitt et al, 1999; Tu et al, 1999) have been implicated in diverse brain disorders, including autism spectrum disorders (ASD), neurological and psychiatric symptoms of Phelan-McDermid syndrome (PMS), schizophrenia, intellectual disability and mania GABAergic neurons in the striatum have dendritic spines where Shank may play important roles in the regulation of spinogenesis and axospinous synapse functions (Harris and Weinberg, 2012; O’Rourke et al, 2012)

Methods

Results

Conclusion