Homeostatic regulation of glutamatergic transmission by dopamine D4 receptors

Alterations of synaptic transmission have been considered a core feature of mental disorders; thus, we examined the role of dopamine D-4 receptors, which is highly implicated in attention-deficit hyperactivity disorder and schizophrenia, in regulating synaptic functions of prefrontal cortex, a brain region critical for cognitive and emotional processes. We found that D-4 stimulation caused a profound depression or potentiation of AMPA receptor-mediated excitatory synaptic transmission in prefrontal cortex pyramidal neurons when their activity was elevated or dampened, respectively, which was accompanied by a D-4-induced decrease or increase of AMPARs at synapses. The dual effects of D-4 on AMPAR trafficking and function was dependent on the D-4-mediated bidirectional regulation of CaMKII activity via coupling to distinct signaling pathways, which provides a unique mechanism for D-4 receptors to serve as a homeostatic synaptic factor to stabilize cortical excitability.