Background: People with schizophrenia misinterpret the environment, leading to inappropriate assignment? of meaning to irrelevant stimuli and inability to recognize relevant social cues. Although the process of? assigning meaning is beyond our understanding, the ability to detect change can be reduced to a series of? sequential operations including 1) registration of sensory input; 2) encoding of qualitative features 3) echoic? stimulus memory; 4) comparison of sequential inputs and 5) deviance determination. These operations are? abnormal in schizophrenia as measured with electrophysiological responses using auditory event related? potentials (ERPs). Central Hypothesis: The inability to form normal ERPs in schizophrenia reflects an? inability to relay basic sensory input from the external world with high fidelity. This reduction of accurate? sensory input leads to misinterpretation and inability to process information for learning, memory and? executive function. Therefore, understanding the basic neurobiology of impaired sensory encoding using? mouse ERPs will inform treatments for cognitive deficits in schizophrenia. Research Project: We previously? demonstrated mouse analogues of the human P50, N100, mismatch negativity (MMN) and P3a. Mice that? express a constitutively active Gsa G-protein subunit have reduced amplitude of the mouse N100 analogue,? similar to schizophrenia. However, the role of the Gsa mutation in deviance detection is not known.? Additionally, NMDA receptor antagonists disrupt MMN in mice, recreating the schizophrenia endophenotype.? Also, mice with reduced expression of the presynaptic glutamate related protein dysbindin, which is linked to? schizophrenia by post-mortem and genetic analyses, display altered electrophysiology in hippocampal slice? preparations. However, the role of dysbindin in deviance detection is not known. The proposed project will? determine roles of Gsa and dysbindin expression in deviance related ERPs and use these models to? investigate novel schizophrenia treatments.
Aim 1 will determine the extent to which alterations in Gsa and? dysbindin expression disrupt deviance related ERPs, Aim 2 will determine the extent to which these? mutations alter auditory evoked gamma oscillations and Aim 3 will determine the extent to which they alter? auditory induced theta oscillations in mice. Environment: Studies will be performed in the laboratory of? Steven Siegel and will be integrated with animal and human studies in the proposed Conte Center. This? laboratory has the expertise and experience to perform all proposed studies. Future Directions: Completion? of proposed work will further understanding of the roles of dysbindin polymorphisms and dysregulation of? intracellular cAMP signal transduction in sensory perception in schizophrenia. Future studies will incorporate? behavioral tasks to clarify the ways in which abnormal sensory ERPs contribute to complex cognitive deficits.?
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