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

Abstract

The mesocortical dopamine inputs from ventral tegmental area to prefrontal cortex (PFC) 2 is involved in many cognitive functions, such as motivation (1) D 4 receptor is of particular interest because of its potent affinity to atypical antipsychotics, such as clozapine, which has fewer extrapyramidal side effects compared with typical antipsychotics with D 2 antagonism (8, 9). The D 4 R gene polymorphisms with variable tandem repeats have been implicated in the prevalence of several mental disorders, including attention deficit-hyperactivity disorder (ADHD) (10, 11), Tourette syndrome (12), and substance abuse (13,14). Moreover, human studies suggest that the gene polymorphisms correlate with the PFC gray matter volume (15) and responsiveness to medication in ADHD patients (16). In animal studies, mice lacking D 4 R show cortical hyperexcitability (17), decreased novelty exploration (18), and increased locomotor sensitivity to psychostimulants (19). These findings support the essential role of D 4 R in normal PFC functioning as well as in many neuropsychiatric disorders.Growing evidence suggests a homeostatic function of D 4 receptors in PFC. Behavioral studies show that a D 4 antagonist may enhance or suppress working memory depending on the base-line performance (20). Our previous studies have identified two homeostatic targets of D 4 : CaMKII and AMPAR (21,22). At high neuronal activity, D 4 suppresses AMPAR-mediated synaptic transmission by decreasing CaMKII activity. Conversely, at low neuronal activity, D 4 potentiates AMPAR trafficking and function by increasing CaMKII enzymatic activity and synaptic redistribution (22,23). Such a D 4 -mediated, state-dependent homeostatic mechanism could be highly relevant to the pathophysiology of ADHD and schizophrenia, in which weakened D 4 function and dysregulation of glutamatergic transmission have been implicated. In this study, we have dissected out the mechanisms downstream of CaMKII that are responsible for the activity-dependent bi-directional regulation of AMPARs by D 4 in PFC pyramidal neurons. MATERIALS AND METHODSSynaptic Current Recording in PFC Cultures-All experiments were carried out with the approval of the State University of New York at Buffalo Animal Care Committee. PFC cultures were prepared from 18-day rat embryos and maintained for 3-4 weeks in vitro. In some experiments, cultures were pretreated with the GABA A R antagonist bicuculline (10 M, 2 h) or TTX (0.5 M, 2 h) to elevate or dampen basal neuronal activity, respectively. AMPAR-mediated mEPSC was recorded as described previously (24). The internal solution contained 130 mM cesium methanesulfonate, 10 mM CsCl, 4 mM NaCl, 1 mM MgCl 2 , 10 mM HEPES, 5 mM EGTA, 2.2 mM lidocaine, 12 mM phosphocreatine, 5 mM MgATP, 0.5 mM Na 2 GTP, 0.1 mM leupeptin, pH 7.2-7.3, 265-270 mOsm. The external solution contained 127 mM NaCl, 5 mM KCl, 2 mM MgCl 2 , 2 mM CaCl 2 , 12 * This work was supported, in whole or in part, by National Institutes of Health Grant MH84233 (to Z. Y.

Restoration of Glutamatergic Transmission by Dopamine D4 Receptors in Stressed Animals

“…On the other hand, D 4 potently increases CaMKII activity in repeatedly stressed animals, which is important for the D 4 enhancement of AMPAR responses. It further confirms that the D 4 -induced homeostatic regulation of AMPARs depends on the activity-dependent bi-directional regulation of CaMKII (23,24,38).…”

“…Activation of D 4 reduces the potentiated AMPAR responses in acutely stressed animals and enhances the depressed AMPAR responses in repeatedly stressed animals. The restoration of synaptic strength to the control level by D 4 in stress conditions supports the notion that D 4 serves as a homeostatic synaptic factor to stabilize cortical excitability (23,24).…”

“…CaMKII Is Involved in the D 4 Regulation of AMPAR Transmission in Stressed Animals-Our previous studies have shown that D 4 exerts an activity-dependent bi-directional regulation of CaMKII (38), which is critical for the D 4 -induced homeostatic regulation of AMPARs in vitro (23,24). Thus, we tested the role of CaMKII in the D 4 actions in stressed animals.…”

“…Dysfunction of glutamatergic transmission is considered as the core feature and fundamental pathology of mental disorders (20 -22). Recently we have demonstrated that D 4 stimulation causes a profound depression of AMPA receptor (AMPAR) responses in PFC pyramidal neurons when their activity is elevated in vitro and causes a marked potentiation of AMPAR responses when their activity is dampened in vitro (23,24). It suggests that D 4 receptors may use the homeostatic control of glutamatergic transmission to stabilize the activity of PFC circuits.…”

Impaired α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor Trafficking and Function by Mutant Huntingtin

“…It suggests that a big portion of GluR1/2 heteromers is independent of the microtubule motor KIF5. Consistently, whole-cell recordings have found that blocking KIF5 function only leads to 35-40% reduction of AMPAR-EPSC (30,31), which may attributable to the loss of GluR2/3 channel transport on microtubules. The lack of effect on surface GluR1 in HD mice may be due to the small portion of GluR1 (in GluR1/2 and GluR1/1 channels) that is dependent on the MT/KIF5-based transport.…”