Enhancing inhibitory synaptic function reverses spatial memory deficits in Shank2 mutant mice

• Published in: Neuropharmacology Vol. 112; no. Pt A; pp. 104 - 112
• Main Authors: Lim, Chae-Seok, Kim, Hyopil, Yu, Nam-Kyung, Kang, Sukjae Joshua, Kim, TaeHyun, Ko, Hyoung-Gon, Lee, Jaehyun, Yang, Jung-eun, Ryu, Hyun-Hee, Park, Taesung, Gim, Jungsoo, Nam, Hye Jin, Baek, Sung Hee, Wegener, Stephanie, Schmitz, Dietmar, Boeckers, Tobias M., Lee, Min Goo, Kim, Eunjoon, Lee, Jae-Hyung, Lee, Yong-Seok, Kaang, Bong-Kiun
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2017
• Subjects: Animals; Autism Spectrum Disorder - physiopathology; Autism spectrum disorders; CA1 Region, Hippocampal - physiology; Gabra2; I/E ratio; Inhibitory Postsynaptic Potentials; Male; Maze Learning - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - physiology; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; Shank2; Social Behavior; Spatial memory; Spatial Memory - physiology; Autism spectrum disorders; Shank2; I/E ratio; Gabra2; Spatial memory
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2016.08.016

Autism spectrum disorders (ASDs) are a group of developmental disorders that cause variable and heterogeneous phenotypes across three behavioral domains such as atypical social behavior, disrupted communications, and highly restricted and repetitive behaviors. In addition to these core symptoms, other neurological abnormalities are associated with ASD, including intellectual disability (ID). However, the molecular etiology underlying these behavioral heterogeneities in ASD is unclear. Mutations in SHANK2 genes are associated with ASD and ID. Interestingly, two lines of Shank2 knockout mice (e6-7 KO and e7 KO) showed shared and distinct phenotypes. Here, we found that the expression levels of Gabra2, as well as of GABA receptor-mediated inhibitory neurotransmission, are reduced in Shank2 e6-7, but not in e7 KO mice compared with their own wild type littermates. Furthermore, treatment of Shank2 e6-7 KO mice with an allosteric modulator for the GABAA receptor reverses spatial memory deficits, indicating that reduced inhibitory neurotransmission may cause memory deficits in Shank2 e6-7 KO mice. This article is part of the Special Issue entitled ‘Ionotropic glutamate receptors’. •Expression of Gabra2 gene coding GABAA receptor α2 subunit was reduced in Shank2 e6-7 KO mice, but not in Shank2 e7 KO mice.•GABAA receptor-mediated synaptic transmission was impaired in Shank2 e6-7 KO mice, resulting in reduced I/E ratio.•A GABAA receptor α2 agonist L838,417 restored the impaired I/E ratio in Shank2 e6-7 KO mice.•L838,417 treatment reversed spatial memory deficits in Shank2 e6-7 KO mice without affecting the social deficit.