The Role Of Sorbs2 Gene In Dendritic Development,Synaptic Transmission And Cognitive Impairment

Intellectual disability(ID)is a common neurodevelopmental disorder characterized by impaired intellectual and adaptive functioning.ID is estimated to affect 1%-3%of the population worldwide.It severly affects the patients’ daily life.Both environmental insults and genetic defects contribute to the etiology of intellectual disability.Copy number variations of Sorbs2 have been linked to intellectual disability.However,the neurobiological function of Sorbs2 in the brain is unknown.The Sorbs2 gene encodes Arg/c-Abl kinase binding protein 2(ArgBP2)in non-neuronal tissues and is alternatively spliced in the brain to encode nArgBP2 protein.Our aim is to study the neurobiological function of nArgBP2 in the brain,specifically to study its role in synaptic development and brain disoders.We employed genetic,morphological,electrophysiological and behavioral approaches to characterize potential defects in the Sorbs2 conditional knockout mice.We have several findings as described below.First,high expression level of nArgBP2 in dentate gyros with a unique pattern.The nArgBP2 was highly expressed in several brain areas,including cortex,amygdala,and hippocampus.In hippocampus,nArgBP2 was enriched in the outer cone-third of the molecular layer in dentate gyrus.In cultured hippocampal neurons,nArgBP2 proteins were found to be colocalized with F-actin at dendritic spines and growth cones,and were also colocalized well with the excitatory postsynaptic scaffolding protein PSD95 but rarely overlapped with inhibitory postsynaptic scaffolding protein gephyrin.Second,the Sorbs2 knockout mice exhibit normal brain structures.We generated a Sorbs2 conditional knockout(KO)muse model to study the neurobiological function of nArgBP2 in the brain.Morphological characterization of the entire brain showed no difference between wild type(WT)and KO mice.KO mice also exhibited normal cortex and DG molecular layer lamination.Third,genetic deletion of Sorbs2 in mice led to reduced dendritic complexity and decreased frequency of AMPAR-mediated spontaneous miniature EPSCs in dentate gyrus granule cells.Fourth,impairment of cognitive functions in Sorbs2 KO mice.Behavioral characterization revealed that Sorbs2 deletion led to a reduced acoustic startle response,defective long-term object recognition memory and contextual fear memory.Taken together,our findings demonstrate,for the first time,an important role for nArgBP2 in neuronal dendritic development and excitatory synaptic transmission.Our study provides important information for further exploration of neurobiological basis of Sorbs2 deficiency in intellectual disability.