Molecular And Cellular Mechanisms Of Drd2 Regulation Of Synaptic Pruning In ACC Brain Region

Synapses are the main parts of communication between neurons,and proper synaptic formation is the basis for the normal operation of neural circuits.Impairment of synaptic structure and function is one of the pathophysiological mechanisms of many neuropsychiatric diseases.Synaptic pruning during adolescence plays an important role in neural development and synaptic plasticity.Abnormal synaptic pruning can lead to various brain disorders,such as schizophrenia,autism and anxiety.Dopamine D2 receptor(Drd2)is associated with many neuropsychiatric diseases and is the target of antipsychotic drugs.In this study,we studied the time course of different types of dendritic spines in SR-Drd2+/-rats,and found that Drd2 regulates synaptic pruning,mainly affecting the density of mushroom type and stubbly type dendritic spines after 3 weeks.Furthermore,studies on the downstream pathways of Drd2 show that Drd2 regulates synaptic pruning through the mTOR signaling pathway which affecting protein synthesis and autophagy and.By inhibiting the mTOR pathway in adolescence,the morphological and functional abnormalities caused by Drd2 down-regulation are rescued,further suggesting that Drd2 mainly regulates synaptic pruning through the mTOR signaling pathway.At the same time,we found acute inhibition of Drd2 in ACC brain region and induction of LTD by whole-cell patch clamp,and found impaired synaptic plasticity associated with LTD in Drd2-positive neurons but not in negative neurons.Next,to further study the cellular mechanism of Drd2 regulating synaptic pruning,we used Drd2 sh RNA to inject into the deep ACC brain region of Drd2-Cre rats during adolescence,and constructed Drd2-KD rats that specifically down-regulated the expression level of Drd2 in Drd2-positive neurons in the deep ACC brain region.Morphological and functional studies showed that Drd2-KD rats showed increased density of dendritic spines,increased afferent intensity of excitatory synapses,E-I imbalance and hyperexcitability of neurons,further suggesting that Drd2 regulates synaptic pruning mainly through postsynaptic autonomic mechanisms.Subsequent behavioral tests found that the adult Drd2-KD rats showed anxiety-like behaviors,suggesting that the Drd2-positive neurons deep in ACC should be a key component of anxiety-related neural circuits.In conclusion,this paper reveals the important role of Drd2 in cortical synaptic pruning.It was elucidated that Drd2 regulates synaptic pruning,which is mainly related to mTOR signaling pathway mediated synaptic plasticity,protein synthesis,autophagy and other molecules and neuronal autonomic mechanisms,providing a new perspective for Drd2-related pathological mechanisms of neuropsychiatric diseases.