Metabotropic glutamate2/3 (mGlu2/3) receptors, schizophrenia and cognition

Recently, a metabotropic glutamate(2/3) (mGlu(2/3)) receptor agonist prodrug was found to improve both the positive and negative symptoms of schizophrenic patients. Thus far, however, definitive data directly describing the effects of mGlu(2/3) receptor agonists on cognition in schizophrenic patients is lacking. In this review, we will first describe the location of mGlu(2) and mGlu(3) receptors with respect to cellular compartments in cortical circuits of both the prefrontal cortex and the hippocampal formation. We will then address the function of mGlu(2) and mGlu(3) receptors in both macrocircuits and microcircuits involving the prefrontal cortex and hippocampal formation. Imbalance within and between macrocircuits, including the re-entrant cortico-striatal-thalamic loops; the trisynaptic organization of the hippocampal formation; and the ascending reticular activating system/monoaminergic brainstem nuclei projecting throughout the neural axis, appear central to understanding both the pathophysiology and therapeutic approaches for treating the pervasive cognitive dysfunction associated with schizophrenia. Understanding the function of mGlu(2) and mGlu(3) receptors in these macrocircuits also may provide answers to currently conflicting data between some preclinical studies and the clinical studies seemingly predicting impairment and improvement in cognitive function with activation of mGlu(2) and mGlu(3) receptors.