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J Neurophysiol 97: 1196-1208, 2007. First published December 20, 2006; doi:10.1152/jn.00400.2006
0022-3077/07 $8.00

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Acute Clozapine Suppresses Synchronized Pyramidal Synaptic Network Activity by Increasing Inhibition in the Ferret Prefrontal Cortex

¹Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania; and ²Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut

Submitted 16 April 2006; accepted in final form 18 December 2006

Recent studies have indicated that impaired neural circuitry in the prefrontal cortex is a prominent feature of the neuropathology of schizophrenia. Clozapine is one of the most effective antipsychotic drugs used for this debilitating disease. Despite its effectiveness, the mechanism by which clozapine acts on prefrontal cortical circuitry remains poorly understood. In this study, in vitro multiple whole cell recordings were performed in slices of the ferret prefrontal cortex. Clozapine, which effectively inhibited the spontaneous synchronized network activities in the prefrontal neurons, achieved the suppressive effect by decreasing the recurrent excitation among pyramidal neurons and by enhancing the inhibitory inputs onto pyramidal cells through a likely network mechanism. Indeed, under the condition of disinhibition, the depressing effects were reversed and clozapine enhanced the recurrent excitation. These results suggest that the therapeutic actions of clozapine in alleviating the positive symptoms of schizophrenia are achieved, at least partially, through the readjustment of synaptic balance between the excitation and inhibition in the prefrontal cortical circuitry.

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