Mechanisms Underlying Synaptic Degeneration In Alzheimer's Disease And Social Behavior

BackgroundThe entorhinal cortex(EC)plays an important role in connecting the hippocampus and neocortex.EC and hippocampal circuit is most vulnerable in the early stage of Alzheimer's disease(AD)and contributing to memory impairment.ObjectiveExcitatory pyramidal neurons in the EC layer II region(ECIIPN)form functional excitatory synapses with CA1 parvalbumin-positive inhibitory neurons(CA1PV)and undergo selective degeneration in the early stages of AD.However,the molecular mechanisms underlying degeneration of ECIIPN synapses remain unknown.MethodsHere we selectively detected the kinase activity of death-associated protein kinase 1(DAPK1)and we established selective DAPK1 genetic inhibition in ECIIPN of AD mice.We used patch-clamp,optogenetic and in vivo recording to investigate whether selective inhibition of DAPK1 can rescue ECIIPN synaptic degeneration and spatial learning and memory of AD mice.ResultsOur results show that DAPK1 is selectively activated in ECIIPN of AD mice.Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECIIPN-CAIpv synaptic loss,excitatory and inhibitory imbalance in the CA1 circuits of AD mice and improves spatial learning and memory in AD mice.ConclusionsOur results demonstrated that activation of DAPK1 in ECIIPN contributes to a memory loss in AD and hence warrants a promising target for the treatment of AD.BackgroundImpairment of social behavior is one of core symptoms of psychiatric diseases,including schizophrenia,autism,depression and anxiety.It's widely known that medial prefrontal cortex?basolateral amygdala and ventral hippocampus are implicated in social behavior.ObjectiveThere are abundant projections among mPFC-BLA-vHPC regions.However,little is known about whether mPFC-BLA-vHPC circuits participate in regulation of social behavior and if yes,what's the mechanism?MethodsHere we investigated the functional connectivity of mPFC-BLA-vHPC circuits by using in vivo recording in free-moving mice during social interaction and social recognition behavior.As ErbB4 is a susceptibility gene of major depression and schizophrenia,next we used T796G mice for acute inhibition of ErbB4 during social behavior,to investigate if impaired ErbB4 signaling disrupts social behavior of mice,activity of mPFC,BLA,and vHPC regions and synchrony of mPFC-BLA-vHPC circuits during social behavior.ResultsOur results show that activity of mPFC,BLA,and vHPC regions in mice brain are reduced during social interaction behavior,furthermore,synchronies among these three regions are reduced too.During social recognition,only synchrony between vHPC and mPFC decreased,while there is no significant difference of BLA and mPFC,or BLA and vHPC.Acute inhibition of ErbB4 impairs social function of mice.During social interaction,synchrony of mPFC-vHPC and vHPC-BLA are disrupted after inhibiting ErbB4 kinase activity.During social recognition,inhibition of ErbB4 impaired synchrony of vHPC-mPFC circuit.ConclusionsOur results demonstrated that mPFC-BLA-vHPC circuits participate in social behavior and are regulated by NRG1/ErbB4 signal.Impaired ErbB4 and thus mPFC-BLA-vHPC synchrony might be a pathophysiological mechanism of social deficits of psychiatric diseases.