Dopamine D4 receptors regulate AMPA receptor trafficking and glutamatergic transmission in GABAergic interneurons of prefrontal cortex.

GABAergic interneurons in prefrontal cortex (PFC) play a critical role in cortical circuits by providing feedforward and feedback inhibition and synchronizing neuronal activity. Impairments in GABAergic inhibition to PFC pyramidal neurons have been implicated in the abnormal neural synchrony and working memory disturbances in schizophrenia. The dopamine D(4) receptor, which is strongly linked to neuropsychiatric disorders, such as attention deficit-hyperactivity disorder (ADHD) and schizophrenia, is highly expressed in PFC GABAergic interneurons, while the physiological role of D(4) in these interneurons is largely unknown. In this study, we found that D(4) activation caused a persistent suppression of AMPAR-mediated synaptic transmission in PFC interneurons. This effect of D(4) receptors on AMPAR-EPSC was via a mechanism dependent on actin/myosin V motor-based transport of AMPA receptors, which was regulated by cofilin, a major actin depolymerizing factor. Moreover, we demonstrated that the major cofilin-specific phosphatase Slingshot, which was activated by calcineurin downstream of D(4) signaling, was required for the D(4) regulation of glutamatergic transmission. Thus, D(4) receptors, by using the unique calcineurin/Slingshot/cofilin signaling mechanism, regulate actin dynamics and AMPAR trafficking in PFC GABAergic interneurons. It provides a potential mechanism for D(4) receptors to control the excitatory synaptic strength in local-circuit neurons and GABAergic inhibition in the PFC network, which may underlie the role of D(4) receptors in normal cognitive processes and mental disorders.