Cellular mechanisms for dopamine D ₄ receptor-induced homeostatic regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors

Aberrant dopamine D ₄ receptor function has been implicated in mental illnesses, including schizophrenia and attention deficit-hyperactivity disorder. Recently we have found that D ₄ receptor exerts an activity-dependent bi-directional regulation of AMPA receptor (AMPAR)-mediated synaptic currents in pyramidal neurons of prefrontal cortex (PFC) via the dual control of calcium/calmodulin kinase II (CaMKII) activity. In this study, we examined the signaling mechanisms downstream of CaMKII that govern the complex effects of D ₄ on glutamatergic transmission. We found that in PFC neurons at high activity state, D ₄ suppresses AMPAR responses by disrupting the kinesin motor-based transport of GluR2 along microtubules, which was accompanied by the D ₄ reduction of microtubule stability via a mechanism dependent on CaMKII inhibition.Onthe other hand, in PFC neurons at the low activity state, D ₄ potentiates AMPAR responses by facilitating synaptic targeting of GluR1 through the scaffold protein SAP97 via a mechanism dependent on CaMKII stimulation. Taken together, these results have identified distinct signaling mechanisms underlying the homeostatic regulation of glutamatergic transmission by D ₄ receptors, which may be important for cognitive and emotional processes in which dopamine is involved.