Increasing evidence has suggested that the interaction between dopaminergic and glutamatergic systems in prefrontal cortex (PFC) plays an important role in normal mental functions and neuropsychiatric disorders. In this study, we examined the regulation of NMDA-type glutamate receptors by the PFC dopamine D4 receptor (one of the principal targets of antipsychotic drugs). Application of the D4 receptor agonist PD168077 caused a reversible decrease of the NMDA receptor (NMDAR)-mediated current in acutely isolated and cultured PFC pyramidal neurons, an effect that was blocked by selective D4 receptor antagonists. Furthermore, application of PD168077 produced a potent reduction of the amplitude (but not paired-pulse ratio) of evoked NMDAR EPSCs in PFC slices. The D4 modulation of NMDA receptors in PFC involved the inhibition of protein kinase A, activation of protein phosphatase 1 and the ensuing inhibition of active Ca2+-calmodulin-dependent kinase II (CaMKII). Moreover, PD168077 reduced the surface expression of NMDARs and triggered the internalization of NMDARs in a manner dependent on CaMKII activity. These results identify a mechanistic link between D4 and NMDA receptors in PFC pyramidal neurons, suggesting that D4 receptors may play an important role in modulating synaptic plasticity and thus cognitive and emotional processes in PFC circuits.
The D 4 modulation of GABA A receptor currents was blocked by protein kinase A (PKA) activation and occluded by PKA inhibition. Inhibiting the catalytic activity of protein phosphatase 1 (PP1) also eliminated the effect of PD168077 on GABA A currents. Furthermore, disrupting the association of the PKA/PP1 complex with its scaffold protein Yotiao significantly attenuated the D 4 modulation of GABA A currents, suggesting that Yotiao-mediated targeting of PKA/PP1 to the vicinity of GABA A receptors is required for the dopaminergic signaling. Together, our results show that activation of D 4 receptors in PFC pyramidal neurons inhibits GABA A channel functions by regulating the PKA/PP1 signaling complex, which could underlie the D 4 modulation of PFC neuronal activity and the actions of antipsychotic drugs.
The action of glutamate in CNS is mediated by the activation of metabotropic and ionotropic receptors. The metabotropic glutamate receptors (mGluRs) are highly enriched in prefrontal cortex (PFC) -a brain region critically involved in the regulation of cognition and emotion. Emerging evidence has suggested that mGluRs are viable drug targets for neuropsychiatric disorders associated with PFC dysfunction. However, the mGluR-mediated signalling in PFC remains unclear. To understand the physiological functions of postsynaptic group II mGluRs (mGluR2/3) in PFC neurones, we investigated the molecular and cellular mechanisms underlying the regulation of NMDA receptor channels by group II mGluRs. We found that APDC, a highly selective and potent group II mGluR agonist, reversibly increased NMDAR currents in acutely dissociated PFC pyramidal neurones. Selective group II mGluR antagonists, but not group I mGluR antagonists, blocked APDC-induced enhancement of NMDAR currents, suggesting the mediation by mGluR2/3 receptors. The APDC effect on NMDAR currents was independent of Mg 2+ block or membrane voltages, and primarily targeted NR2A subunits containing NMDARs. While changing protein kinase A levels was without effect, inhibiting protein kinase C (PKC) or dialysis with Ca 2+ chelators largely blocked the mGluR2/3 modulation of NMDAR currents. In contrast, inhibiting protein tyrosine kinases, cyclin-dependent kinase 5, Ca 2+ /calmodulindependent kinase II or the Ca 2+ /calmodulin-dependent phosphatase calcineurin failed to do so. Moreover, treatment of PFC slices with APDC significantly increased the PKC activity and PKC phosphorylation of NMDA receptors. These findings suggest that activation of mGluR2/3 receptors potentiates NMDAR channel functions in PFC through a PKC-dependent mechanism. This modulation may be relevant for developing novel mGluR-related pharmacological agents for the treatment of mental illnesses.
It has long been recognized that muscarinic acetylcholine receptors (mAChRs) are crucial for the control of cognitive processes, and drugs that activate mAChRs are helpful in ameliorating cognitive deficits of Alzheimer's disease (AD). On the other hand, GABAergic transmission in prefrontal cortex (PFC) plays a key role in "working memory" via controlling the timing of neuronal activity during cognitive operations. To test whether the muscarinic and ␥-aminobutyric acid (GABA) system are interconnected in normal cognition and dementia, we examined the muscarinic regulation of GABAergic transmission in PFC of an animal model of AD. Transgenic mice overexpressing a mutant gene for -amyloid precursor protein (APP) show behavioral and histopathological abnormalities resembling AD and, therefore, were used as an AD model. Application of the mAChR agonist carbachol significantly increased the spontaneous inhibitory postsynaptic current (sIPSC) frequency and amplitude in PFC pyramidal neurons from wild-type animals. In contrast, carbachol failed to increase the sIPSC amplitude in APP transgenic mice, whereas the carbachol-induced increase of the sIPSC frequency was not significantly changed in these mutants. Similar results were obtained in rat PFC slices pretreated with the -amyloid peptide (A). Inhibiting protein kinase C (PKC) blocked the carbachol enhancement of sIPSC amplitudes, implicating the PKC dependence of this mAChR effect. In APP transgenic mice, carbachol failed to activate PKC despite the apparently normal expression of mAChRs. These results show that the muscarinic regulation of GABA transmission is impaired in the AD model, probably due to the A-mediated interference of mAChR activation of PKC. Alzheimer's disease (AD)1 is a devastating neurodegenerative disorder. Several prominent features consistently found in AD patients include: degeneration of basal forebrain cholinergic neurons and ensuing deficient cholinergic functions in cortex and hippocampus, extracellular protein aggregates containing -amyloid peptides (A) in these cholinergic target areas, and impairments in mental functions that are characterized by the loss of memory (1-3). So far, the most effective therapeutic strategy in AD treatment is to enhance cholinergic transmission (4, 5). It has long been recognized that muscarinic acetylcholine receptors (mAChRs) are crucial for the control of high level cognitive processes (6, 7). Drugs that antagonize mAChRs worsen the performance of human subjects and animals in learning and memory tasks (8, 9), while drugs that activate mAChRs are helpful in ameliorating cognitive deficits of AD (10, 11). Despite the discovery of correlation between cholinergic hypofunction and AD, the cellular and molecular mechanisms underlying the function and dysfunction of mAChRs in normal cognition and dementia remain elusive.Prefrontal cortex (PFC), one of the major target areas of basal forebrain cholinergic neurons, has long been associated with high-level, "executive" processes (12), particularly a form of ...
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