Cellular Mechanisms for Dopamine D4 Receptor-induced Homeostatic Regulation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

Zhen Yan,Eunice Y Yuen

doi:10.1074/jbc.m111.221416

Zhen Yan, Eunice Y Yuen

Open Access

https://doi.org/10.1074/jbc.m111.221416

Copy DOI

Abstract

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. On the 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.

Highlights

The mesocortical dopamine inputs from ventral tegmental area to prefrontal cortex (PFC)2 is involved in many cognitive functions, such as motivation [1], reinforcement learning [2], and working memory [3, 4]
Recorded mEPSC, which represents the postsynaptic response to release of individual vesicles of glutamate, in cultured PFC pyramidal neurons pretreated with bicuculline (10 ␮M, 2 h) or TTX (0.5 ␮M, 2 h)
We have revealed the mechanism downstream of calmodulin kinase II (CaMKII) that underlies the unique action of D4 on AMPA receptors in PFC pyramidal neurons (Fig. 6)

Summary

Introduction

The mesocortical dopamine inputs from ventral tegmental area to prefrontal cortex (PFC) is involved in many cognitive functions, such as motivation [1], reinforcement learning [2], and working memory [3, 4]. Mice lacking D4R show cortical hyperexcitability [17], decreased novelty exploration [18], and increased locomotor sensitivity to psychostimulants [19] These findings support the essential role of D4R in normal PFC functioning as well as in many neuropsychiatric disorders. At low neuronal activity, D4 potentiates AMPAR trafficking and function by increasing CaMKII enzymatic activity and synaptic redistribution [22, 23]. Such a D4-mediated, state-dependent homeostatic mechanism could be highly relevant to the pathophysiology of ADHD and schizophrenia, in which weakened D4 function and dysregulation of glutamatergic transmission have been implicated. We have dissected out the mechanisms downstream of CaMKII that are responsible for the activity-dependent bi-directional regulation of AMPARs by D4 in PFC pyramidal neurons

Methods

Results

Conclusion