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.
|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|
|Urban, Kimberly R; Li, Yan-Chun; Gao, Wen-Jun (2013) Treatment with a clinically-relevant dose of methylphenidate alters NMDA receptor composition and synaptic plasticity in the juvenile rat prefrontal cortex. Neurobiol Learn Mem 101:65-74|
|Urban, Kimberly R; Gao, Wen-Jun (2013) Methylphenidate and the juvenile brain: enhancement of attention at the expense of cortical plasticity? Med Hypotheses 81:988-94|
|Wang, H-X; Waterhouse, B D; Gao, W-J (2013) Selective suppression of excitatory synapses on GABAergic interneurons by norepinephrine in juvenile rat prefrontal cortical microcircuitry. Neuroscience 246:312-28|
|Wang, Min-Juan; Li, Yan-Chun; Snyder, Melissa A et al. (2013) Group II metabotropic glutamate receptor agonist LY379268 regulates AMPA receptor trafficking in prefrontal cortical neurons. PLoS One 8:e61787|
|Snyder, Melissa A; Adelman, Alicia E; Gao, Wen-Jun (2013) Gestational methylazoxymethanol exposure leads to NMDAR dysfunction in hippocampus during early development and lasting deficits in learning. Neuropsychopharmacology 38:328-40|
|Xi, Dong; Li, Yan-Chun; Snyder, Melissa A et al. (2011) Group II metabotropic glutamate receptor agonist ameliorates MK801-induced dysfunction of NMDA receptors via the Akt/GSK-3* pathway in adult rat prefrontal cortex. Neuropsychopharmacology 36:1260-74|
|Li, Yan-Chun; Gao, Wen-Jun (2011) GSK-3ýý activity and hyperdopamine-dependent behaviors. Neurosci Biobehav Rev 35:645-54|
|Xi, Dong; Zhang, Wentong; Wang, Huai-Xing et al. (2009) Dizocilpine (MK-801) induces distinct changes of N-methyl-D-aspartic acid receptor subunits in parvalbumin-containing interneurons in young adult rat prefrontal cortex. Int J Neuropsychopharmacol 12:1395-408|
Showing the most recent 10 out of 11 publications