Abstract
Synaptic pruning during adolescence is important for appropriate neurodevelopment and synaptic plasticity. Aberrant synaptic pruning may underlie a variety of brain disorders such as schizophrenia, autism and anxiety. Dopamine D2 receptor (Drd2) is associated with several neuropsychiatric diseases and is the target of some antipsychotic drugs. Here we generate self-reporting Drd2 heterozygous (SR-Drd2+/−) rats to simultaneously visualize Drd2-positive neurons and downregulate Drd2 expression. Time course studies on the developing anterior cingulate cortex (ACC) from control and SR-Drd2+/− rats reveal important roles of Drd2 in regulating synaptic pruning rather than synapse formation. Drd2 also regulates LTD, a form of synaptic plasticity which includes some similar cellular/biochemical processes as synaptic pruning. We further demonstrate that Drd2 regulates synaptic pruning via cell-autonomous mechanisms involving activation of mTOR signaling. Deficits of Drd2-mediated synaptic pruning in the ACC during adolescence lead to hyper-glutamatergic function and anxiety-like behaviors in adulthood. Taken together, our results demonstrate important roles of Drd2 in cortical synaptic pruning.
Highlights
Synaptic pruning during adolescence is important for appropriate neurodevelopment and synaptic plasticity
We further demonstrate that Drd[2] regulates synaptic pruning through cell-autonomous mechanisms involving activation of mTOR signaling in sensitive periods
In this study, we demonstrate important roles of DRD2 in cortical synaptic pruning through time course studies from the control and SR-Drd2+/− rats
Summary
Synaptic pruning during adolescence is important for appropriate neurodevelopment and synaptic plasticity. Time course studies on the developing anterior cingulate cortex (ACC) from control and SR-Drd2+/− rats reveal important roles of Drd[2] in regulating synaptic pruning rather than synapse formation. The heterogeneity of cortical neurons makes it challenging to use regular genetic approaches to study the mechanisms of synapse development in different population of neurons To address this issue, we generated selfreporting Drd[2] heterozygous (abbreviated to SR-Drd2+/−) rats to simultaneously visualize Drd2-positive neurons and downregulate Drd[2] expression. We used the SR-Drd2+/− rats to investigate the roles of Drd[2] in synapse development in anterior cingulate cortex (ACC), a brain region implicated in emotional symptoms of neuropsychiatric diseases such as anxiety and depression[36,37]. Our results reveal mechanisms underlying synaptic pruning and how the deficits of these processes cause brain dysfunction in adulthood
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