Downregulation of glutamatergic and GABAergic proteins in valproric acid associated social impairment during adolescence in mice

• Published in: Behavioural brain research Vol. 316; pp. 255 - 260
• Main Authors: Chau, Davor Kin-Fan, Choi, Angus Yiu-Ting, Yang, Wen, Leung, Wing Nang, Chan, Chun Wai
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2017
• Subjects: Adolescence; Animals; Animals, Newborn; Autism spectrum disorder; Brain-Derived Neurotrophic Factor - metabolism; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Down-Regulation - drug effects; Electron Transport Complex IV - metabolism; Female; GABA Agents - toxicity; Gamma-aminobutyric acid; Linear Models; Locomotion - drug effects; Male; Mice; N-methyl-d-aspartate receptor; Pregnancy; Prenatal Exposure Delayed Effects - chemically induced; Prenatal Exposure Delayed Effects - physiopathology; Rabbits; Receptors, GABA - metabolism; Receptors, Glutamate - genetics; Receptors, Glutamate - metabolism; Social Communication Disorder - etiology; Time Factors; Valproic acid; Valproic Acid - toxicity; GABRA1; GABRB2; Adolescence; DSM-V; BDNF; E; GABRA5; VPA; PND; GAD67; Valproic acid; GAD65; Autism spectrum disorder; NR2B; GABAAR; NR2C; ASD; NR2A; NMDAR; Gamma-aminobutyric acid; N-methyl-d-aspartate receptor
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2016.09.003

•NMDAR subunits 2A, 2B, 2C were downregulated in the cortices of VPA-induced autistic adolescent mice.•GABAAR subunits GABRA1, GABRA5 and GABRB2 were downregulated in the cortices of VPA-induced autistic adolescent mice.•Glutamic acid decarboxylase GAD65 and GAD67 were downregulated in the cortices of VPA-induced autistic adolescent mice.•BDNF was downregulated in the cortices of VPA-induced autistic adolescent mice. The etiology of Autism Spectrum Disorder (ASD) remains controversial. Deficits in social communication are one of the key criteria for ASD diagnosis. Valproic acid (VPA), which is an anti-epileptic and anti-depressive drug, is one of the teratogens to cause ASD onset. Moreover, synaptic dysfunction is suggested as one of the major causative factor in VPA-induced ASD in vitro and in vivo studies. Herein, this study aimed to determine the excitatory/inhibitory synaptic mRNA and protein expression in VPA-induced autistic mice. Pregnant BALB/c mice were injected peritoneally with a single dose of 600mg/kg VPA on embryonic day (E) 12.5. Social impairment was verified by three chamber sociability tests on postnatal days (PND) 28, 35, 42 and 49. Cortical synaptic mRNA and protein expressions were examined on PND 50. The excitatory synaptic proteins NR2A, NR2B, NR2C were significantly down-regulated by 80.0% (p<0.01), 51.5% (p<0.05) and 81.5% (p<0.05) respectively. Furthermore, the NMDAR expression regulatory protein BDNF was also found to be significantly downregulated by 76.8% (p<0.05). GAD65, GAD67, GABRA1, GABRA5, GABRB2 from the GABAergic inhibitory synaptic pathway were significantly downregulated by 21.3% (p<0.05), 77.0% (p<0.05), 53.9% (p<0.05), 56.9% (p<0.05) and 55.2% (p<0.01) respectively in the cortex of VPA-induced mice. Taken together, our results suggested that synaptic dysfunction might be involved in the social impairments in VPA-induced ASD.