N-methyl-D-aspartate receptor (NMDAR)-mediated glutamate transmission, along with dopamine (DA) and 3-aminobutyric acid (GABA) systems, has long been linked to schizophrenia, but all commonly prescribed antipsychotic agents act on DA receptors. Recent studies indicate that metabotropic glutamate receptor (mGluR) agonists reverse the behavioral effects of the NMDAR antagonist phencyclidine (PCP) and dizocilpine (MK-801) in animal models and in patients with schizophrenia. These studies suggest that mGluR2/3 receptor agonists have antipsychotic properties and may provide a new treatment of schizophrenia. This finding is exciting, but it raises some fundamental questions: Why do mGluR2/3 agonists have the same therapeutic efficacy as D2 receptor antipsychotic agents and by what mechanisms do mGluR2/3 agonists ameliorate behavior? We hypothesize that mGluR2/3 agonists restore the disrupted NMDAR function induced by the MK- 801 blockade by directly regulating the expression and trafficking of NMDAR subunits in the prefrontal circuitry. An integrated approach of in vivo pharmacologic agents, in vitro patch clamp recording, and molecular techniques will be used to test our hypothesis in the MK-801 animal model of schizophrenia. The proposed experiments will provide insights into the underlying mechanisms of mGluR regulation of NMDAR-mediated transmission and will contribute to a better understanding of how mGluR agonists reverse behavioral effects of NMDAR antagonists in animal models and of the underlying molecular pathophysiological characteristics and treatment of schizophrenia.
Recent studies indicate that mGluR agonists have antipsychotic properties and may provide a new treatment of schizophrenia. However, a fundamental question raised is what mechanisms the mGluR2/3 agonists use to ameliorate behaviors. This study will certainly provide insights into the cellular and molecular mechanisms involved in actions of mGluR agonists as potential antipsychotics.
|Xing, Bo; Li, Yan-Chun; Gao, Wen-Jun (2016) GSK3Î² Hyperactivity during an Early Critical Period Impairs Prefrontal Synaptic Plasticity and Induces Lasting Deficits in Spine Morphology and Working Memory. Neuropsychopharmacology 41:3003-3015|
|Xing, Bo; Li, Yan-Chun; Gao, Wen-Jun (2016) Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex. Brain Res 1641:217-33|
|Li, Meng-Lin; Hu, Xi-Quan; Li, Feng et al. (2015) Perspectives on the mGluR2/3 agonists as a therapeutic target for schizophrenia: Still promising or a dead end? Prog Neuropsychopharmacol Biol Psychiatry 60:66-76|
|Li, Meng-Lin; Yang, Sha-Sha; Xing, Bo et al. (2015) LY395756, an mGluR2 agonist and mGluR3 antagonist, enhances NMDA receptor expression and function in the normal adult rat prefrontal cortex, but fails to improve working memory and reverse MK801-induced working memory impairment. Exp Neurol 273:190-201|
|Monaco, Sarah A; Gulchina, Yelena; Gao, Wen-Jun (2015) NR2B subunit in the prefrontal cortex: A double-edged sword for working memory function and psychiatric disorders. Neurosci Biobehav Rev 56:127-38|
|Urban, Kimberly R; Gao, Wen-Jun (2015) Evolution of the Study of Methylphenidate and Its Actions on the Adult Versus Juvenile Brain. J Atten Disord 19:603-19|
|Urban, Kimberly R; Gao, Wen-Jun (2014) Performance enhancement at the cost of potential brain plasticity: neural ramifications of nootropic drugs in the healthy developing brain. Front Syst Neurosci 8:38|
|Chandler, Daniel J; Waterhouse, Barry D; Gao, Wen-Jun (2014) New perspectives on catecholaminergic regulation of executive circuits: evidence for independent modulation of prefrontal functions by midbrain dopaminergic and noradrenergic neurons. Front Neural Circuits 8:53|
|Pitcher, Jonathan; Abt, Anna; Myers, Jaclyn et al. (2014) Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction. J Clin Invest 124:656-69|
|Ferguson, Brielle R; Gao, Wen-Jun (2014) Development of thalamocortical connections between the mediodorsal thalamus and the prefrontal cortex and its implication in cognition. Front Hum Neurosci 8:1027|
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