GRK5 ablation in mice causes dysregulation of m TOR signalling in the prefrontal cortex and ASD-like behavioural phenotype

【作者】 马兰； 王菲菲； 牛兵； 沈敏杰； 刘佩佩； 刘操； 陈颖； 王丽；

【机构】 复旦大学上海医学院药理研究中心；

【摘要】 Autism spectrum disorders(ASDs)comprise a range of disorders that share a core of behavioural deficits in social behaviours.Although the neurological basis underlying these abnormal behaviours is poorly understood,dysfunction of neuronal signalling has been found in many ASDs.Previous studies demonstrated that GRK5,a G protein-coupled receptor(GPCR)kinase,plays many physiological and pathophysiological roles via regulating signalling mediated by GRCRs or non-GPCR proteins.Here we show that Grk5-/-mice exhibit deficits in social behaviours.Morphology,electrophysiological and biochemical analyses of Grk5-/-mice showed the ultrastructural impairment in cortical postsynaptic densities,the excitatory deficit of synaptic function,and overactivation of m TOR signalling in the prefrontal cortex.The treatment with an FDA-approved m TOR inhibitor and an m Glu R5 antagonist prevented the dysregulation of m TOR signalling and the excitatory deficit of synaptic function in Grk5-/-mice.MPEP also ameliorated the social interaction impairment in Grk5-/-mice.Our findings demonstrate a critical role for GRK5 in maintaining the normal cortical connectivity and suggest that a disruption of GRK5 function in the prefrontal cortex may contribute to the pathogenesis of autistic-like behaviours.更多还原

【Abstract】 Autism spectrum disorders(ASDs) comprise a range of disorders that share a core of behavioural deficits in social behaviours.Although the neurological basis underlying these abnormal behaviours is poorly understood,dysfunction of neuronal signalling has been found in many ASDs.Previous studies demonstrated that GRK5,a G protein-coupled receptor(GPCR) kinase,plays many physiological and pathophysiological roles via regulating signalling mediated by GRCRs or non-GPCR proteins.Here we show that Grk5-/-mice exhibit deficits in social behaviours.Morphology,electrophysiological and biochemical analyses of Grk5-/-mice showed the ultrastructural impairment in cortical postsynaptic densities,the excitatory deficit of synaptic function,and overactivation of m TOR signalling in the prefrontal cortex.The treatment with an FDA-approved m TOR inhibitor and an m Glu R5 antagonist prevented the dysregulation of m TOR signalling and the excitatory deficit of synaptic function in Grk5-/-mice.MPEP also ameliorated the social interaction impairment in Grk5-/-mice.Our findings demonstrate a critical role for GRK5 in maintaining the normal cortical connectivity and suggest that a disruption of GRK5 function in the prefrontal cortex may contribute to the pathogenesis of autistic-like behaviours.更多还原