The regulation of NMDA receptors and GABAA receptors in prefrontal cortical neurons by proteins implicated in schizophrenia
MetadataShow full item record
Schizophrenia is characterized by deficits in executive function and working memory. These deficits are associated with altered GABA and glutamate transmission in the prefrontal cortex (PFC). Here, we tested to see the regulation of GABA A receptors and NMDA receptors by proteins implicated in schizophrenia. Specifically, we looked at (1) the regulation of GABA A receptors by dopamine D 4 receptors, (2) the regulation of GABA A receptors by the DISC1 protein and (3) the regulation of NMDA receptors by the DISC1 protein. Our results show that D 4 receptors and DISC1, two proteins implicated in schizophrenia, can alter synaptic current. (1) The GABA A receptor-mediated inhibitory transmission in prefrontal cortex (PFC) is implicated in cognitive processes such as working memory. Our previous study has found that GABA A R current is subject to the regulation of dopamine D 4 receptors, a PFC-enriched neuromodulator critically involved in various mental disorders associated with PFC dysfunction. In this study, we have investigated the cellular mechanism underlying D 4 modulation of GABA A Rs. We found that the density of surface clusters of GABA A R β2/3 subunits was reduced by D 4 , suggesting that the D 4 reduction of GABA A R current is associated with a decrease in functional GABA A Rs at the plasma membrane. Moreover, the D 4 reduction of GABA A R current was blocked by the actin stabilizer phalloidin and was occluded by the actin destabilizer latrunculin, suggesting that D 4 regulates GABA A R trafficking via an actin-dependent mechanism. Cofilin, a major actin depolymerizing factor whose activity is strongly increased by dephosphorylation at Ser 3 , provides the possible link between D 4 signaling and the actin dynamics. Because myosin motor proteins are important for the transport of vesicles along actin filaments, we also tested the potential involvement of myosin in D 4 regulation of GABA A R trafficking. We found that dialysis with a myosin peptide, which competes with endogenous myosin proteins for actin-binding sites, prevented the D 4 reduction of GABA A R current. These results suggest that D 4 receptor activation increases cofilin activity presumably via its dephosphorylation, resulting in actin depolymerization, thus causing a decrease in the myosin-based transport of GABA A R clusters to the surface. (2) Recent genetic studies have identified DISC1 (Disrupted-in-Schizophrenia-1) as one of the most prominent risk factors for schizophrenia (SZ); however it remains unclear how the aberrant DISC1 function leads to the pathogenesis of neuropsychiatric disorders. Despite some progress on understanding the significance of DISC1 in cortical development, little is known about how DISC1 regulates synaptic function in cortical neurons. Since alterations in the cortical GABA system have been strongly linked to the pathophysiology of schizophrenia, one potential target of DISC1 that is critically involved in the regulation of cognition and emotion is the GABA A receptor. We found that cellular knockdown of DISC1 significantly reduced GABA A R-mediated synaptic and ionic currents. These effects were accompanied by a DISC1 siRNA-induced decrease in GABA A R current density. Our results suggest that DISC1 exerts an important impact on GABAergic inhibitory transmission by regulating GABA A R trafficking in the cortex via kinesin 1. Knowledge gained from this study would shed light on how DISC1 and the GABA system are mechanistically linked and how their interactions are critical for maintaining a normal mental state. (3) In this study, we looked at the regulation of excitatory transmission in the prefrontal cortex by Disrupted-in-schizophrenia 1 (DISC1). Since alterations in NMDA receptor function have been strongly linked to the pathophysiology of schizophrenia, one potential target of DISC1 that is critically involved in the regulation of cognition and emotion is the NMDA receptor. We found that cellular knockdown of DISC1 significantly increased NMDAR-mediated ionic currents in pyramidal neurons of prefrontal cortex, which was accompanied by an increase in surface and total NMDAR NR2B subunit expression. These effects of DISC1 knockdown are dependent on PKA and CREB activation with surface expression of NMDARs dependent upon the kinesin motor protein, KIF17. Our results suggest that DISC1 is influential in regulating NMDAR-mediated synaptic transmission and plasticity in the cortex. Knowledge gained from this study would provide insight into the role of DISC1 in maintaining excitatory transmission in the prefrontal cortex. (Abstract shortened by UMI.)
Showing items related by title, author, creator and subject.
Understanding the crosstalk between receptor and non-receptor tyrosine kinase signal transduction pathways and Cx43 gap junctional communication Mitra, Siddhartha S. (2005)The regulation of communication through gap junction channels consistently correlates with regulation of cellular proliferation and differentiation. In fact one of the initial functions attributed to gap junction channels ...
Zhou, Yu (2005)The gating reaction mechanism of fully-liganded NR1/NR2A recombinant NMDARs (expressed in Xenopus oocytes) was investigated by fitting all possible 3-closed, 2-open state non-cyclic kinetic schemes to currents elicited by ...
Melatonin receptors as modulators of GABA(C) and metabotropic glutamate receptors in the optic tectum of Xenopus laevis Prada, Claudia (2005)The overall purpose of this thesis is to investigate the physiological role of the hormone melatonin in the physiology of the Xenopus tectum. For this purpose, calcium dynamics of retinotectal axon terminals and tectal ...