Autistic-Like Behavior and Impairment of Serotonin Transporter and AMPA Receptor Trafficking in N-Ethylmaleimide Sensitive Factor Gene-Deficient Mice

Min-Jue Xie; Keiko Iwata; Yasuyuki Ishikawa; Yuki Nomura; Tomomi Tani; Koshi Murata; Yugo Fukazawa; Hideo Matsuzaki

doi:10.3389/fgene.2021.748627

Autistic-Like Behavior and Impairment of Serotonin Transporter and AMPA Receptor Trafficking in N-Ethylmaleimide Sensitive Factor Gene-Deficient Mice

Front Genet. 2021 Oct 20:12:748627. doi: 10.3389/fgene.2021.748627. eCollection 2021.

Authors

Min-Jue Xie^{1

2

3}, Keiko Iwata^{1

2

3}, Yasuyuki Ishikawa⁴, Yuki Nomura⁵, Tomomi Tani⁵, Koshi Murata⁶, Yugo Fukazawa^{1

2

6}, Hideo Matsuzaki^{1

2

3}

Affiliations

¹ Division of Development of Mental Functions, Research Center for Child Mental Development, University of Fukui, Fukui, Japan.
² Life Science Innovation Center, University of Fukui, Fukui, Japan.
³ United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Osaka University, Osaka, Japan.
⁴ Department of Systems Life Engineering, Maebashi Institute of Technology, Maebashi, Japan.
⁵ School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
⁶ Division of Brain Structures and Function, Department of Morphological and Physiological Sciences, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

Abstract

Autism spectrum disorder (ASD), characterized by profound impairment in social interactions and communication skills, is the most common neurodevelopmental disorder. Many studies on the mechanisms underlying the development of ASD have focused on the serotonergic system; however, these studies have failed to completely elucidate the mechanisms. We previously identified N-ethylmaleimide-sensitive factor (NSF) as a new serotonin transporter (SERT)-binding protein and described its importance in SERT membrane trafficking and uptake in vitro. In the present study, we generated Nsf ^+/- mice and investigated their behavioral, neurotransmitter, and neurophysiological phenotypes in vivo. Nsf ^+/- mice exhibited abnormalities in sociability, communication, repetitiveness, and anxiety. Additionally, Nsf loss led to a decrease in membrane SERT expression in the raphe and accumulation of glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors at the synaptic membrane surface in the hippocampal CA1 region. We found that postsynaptic density and long-term depression were impaired in the hippocampal CA1 region of Nsf ^+/- mice. Taken together, these findings demonstrate that NSF plays a role in synaptic plasticity and glutamatergic and serotonergic systems, suggesting a possible mechanism by which the gene is linked to the pathophysiology of autistic behaviors.

Keywords: AMPA receptor; N-ethylmaleimide-sensitive factor; autism spectrum disorder; behavior; serotonin transporer.