Alterations in the inhibitory circuitry of the pre-frontal cortex (PFC) are thought to underlie some of the cognitive deficits observed in schizophrenia. These alterations particularly concern a subset of GABAergic interneurons that express the calciumbinding protein parvalbumin (PV) as shown in post mortem studies in patients and animal models of the disease (Lewis et al. 2005). To assess the contribution of PV+ interneurons to PFC- dependent behaviours, we selectively blocked the output from those cells via virus-mediated expression of tetanus toxin light chain (TeLC). We found that functional removal of PV+ neurons causes specific impairments in working memory and cognitive flexibility, which represent key cognitive deficits in schizophrenia. As oscillatory brain activity in the theta (4-8 Hz) and gamma (20-80 Hz) frequency range correlates with working memory performance and patients suffering from schizophrenia show alterations in these frequency bands, we measured local field potential oscillations in the PFC and simultaneously in the hippocampus, a brain region implicated in working memory. Preliminary data indicate a significant decrease in PFC theta and gamma activities in the test mice relative to control animals. Interestingly hippocampal activity in the theta and gamma range was also diminished. These results show that PV+ interneurons in the PFC control task relevant neuronal activity in different brain regions engaged with working memory. Impaired signalling from PFC PV+ interneurons may thus underlie the neurophysiological alterations and concurrent cognitive deficits found in schizophrenia.
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