Dopamine D2 Receptor Regulates Cortical Synaptic Pruning

Synaptic pruning during adolescence is key to forming a healthy and adaptive brain.Aberrant synaptic pruning may underlie a variety of brain disorders such as schizophrenia,autism and anxiety.Dopamine D2 receptor(Drd2)is genetically linked to several neuropsychiatric diseases and is the target of antipsychotics.In this thesis,we used a previous laboratory construct of Drd2 self-reporting(SR-Drd2)rats,and by studying SR-Drd2 rats,we found that Drd2 is mainly distributed in the deep anterior cingulate cortex(ACC)and expressed mainly in pyramidal neurons.Here we generate self-reporting Drd2 heterozygous(SR-Drd2^+/-)rats to simultaneously visualize Drd2-positive neurons and downregulate Drd2 expression.We found that the body weight and brain weight of SR-Drd2 rats and SR-Drd2^+/-rats were comparable.We next found normal morphological development of ACC layer 5 Drd2-positive neurons in SR-Drd2 rats and SR-Drd2^+/-rats.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.We found that Drd2 may regulate synaptic pruning through a cellular or biochemical mechanism similar to that of LTD.Deficits of Drd2-mediated synaptic pruning in the ACC during adolescence lead to hyperglutamatergic function and anxiety-like behaviors in adulthood.Taken together,our results demonstrate important roles of Drd2 in cortical synaptic pruning and may shed light on the pathophysiological mechanisms of neuropsychiatric diseases.