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Principal Investigator: Kazutoshi Nakazawa
Organization: SOUTHERN RESEARCH INSTITUTE
Fiscal Year: 2020
Award: $793,787
Funding agency: National Institute of Mental Health
Abstract
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.
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