Downregulation of glutamatergic and GABAergic proteins in valproric acid associated social impairment during adolescence in 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.
School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
Davor Kin-Fan
DK
Chau
School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
Angus Yiu-Ting
AY
Choi
School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
Wen
W
Yang
School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
Wing Nang
WN
Leung
School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong. Electronic address: francischan.2010@gmail.com.
Chun Wai
CW
Chan
D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D018682:GABA Agents / Q000633:toxicity*; D016014:Linear Models; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000503:physiopathology*; D011817:Rabbits; D018079:Receptors, GABA / Q000378:metabolism; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism*; D000067404:Social Communication Disorder / Q000209:etiology*; D013997:Time Factors; D014635:Valproic Acid / Q000633:toxicity*
D019208:Brain-Derived Neurotrophic Factor; D018682:GABA Agents; D018079:Receptors, GABA; D017470:Receptors, Glutamate; D014635:Valproic Acid; D003576:Electron Transport Complex IV
Adolescence; Autism spectrum disorder; Gamma-aminobutyric acid; N-methyl-d-aspartate receptor; Valproic acid