Abnormal neuronal synchrony at gamma range, often observed in schizophrenia, may be associated with cognitive deficits. Although evidence suggests that cortical fast-spiking interneurons targeting pyramidal cells may be involved in neuronal synchrony, cellular basis of abnormal neuronal synchrony in schizophrenia remains to be identified. We recently demonstrated that early postnatal deletion of NMDA receptors in cortical and hippocampal interneurons, majority of which are parvalbumin containing, was sufficient to trigger several pathophysiological features in mice that resemble human schizophrenia. The mutant mice exhibit several behavioral cognitive-like deficits and prepulse inhibition of the startle reflex. They also display a diminished spike synchrony between cortical pyramidal cells and a deficit in tone-evoked gamma frequency oscillatory activity of local field potentials in auditory cortex, measured by in vivo recordings. It is crucial to delineate the underlying mechanisms of the synchronous firing impairment of postsynaptic neurons following NMDA receptor ablation in cortical interneurons. We recently discovered that glycogen synthase kinase 3 (GSK3) is up- regulated and Cav2.1 (P/Q-type) channel currents are diminished in NMDAR-deleted fast-spiking interneurons of the mutant mice. Furthermore, inhibition of GSK3 activity augmented Cav2.1 channel currents and largely ameliorates the deficit in synchronized GABA release ex vivo. We hypothesize that that GSK3 up-regulation in the NMDA receptor-deficient fast-spiking interneurons down-regulates Cav2.1 channel function, which impairs synchronized GABA release and synchronized oscillations in the cortex producing cognitive dysfunction. The objective of this application is to determine whether dysregulation of GSK3 and Cav2.1 channels in the NMDA receptor-deleted fast-spiking neurons is crucial for an impaired synchronized GABA release and whether functional restoration of these molecules rescues not only in vivo abnormal neuronal synchrony but also behavioral cognitive dysfunction. The proposed studies may yield new insights into cellular mechanisms of cortical neuronal synchrony, potentially leading to development of novel drugs for cognitive dysfunction of schizophrenics, which is currently medically intractable.
Although the mechanism underlying cognitive dysfunction in schizophrenia is poorly understood, recent evidence has indicated that schizophrenia is associated with abnormal amplitude and synchrony of neuronal oscillatory activity, in particular, at gamma frequencies. This project addresses potential cellular mechanisms of abnormal cortical gamma neuronal synchrony in murine NMDA receptor hypofunction model of schizophrenia. This project is highly relevant to NIH's mission, because the proposed research might play an important role in developing new therapeutic targets for cognitive dysfunction of schizophrenics.
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