Date of Award
Doctor of Philosophy (PhD)
Steven J. Siegel
Autism and schizophrenia are neurodevelopmental disorders which both have highly disabling negative and cognitive symptoms with few effective treatments. A challenge to developing effective therapeutics is a dearth of pre-clinical models. Part of the difficulty in developing predictive models is that the symptoms being treated are complex, and difficult to reduce to a simple behavioral task. Therefore, the use of endophenotypes from methods such as EEG presents a new promising avenue for a model of complex human behaviors pre-clinically. New evidence suggests that autism and schizophrenia have reliable electrophysiological endophenotypes, some of which have been correlated to negative and cognitive symptoms. These endophenotypes therefore represent a possible new pathway for understanding the disrupted circuits in both diseases and developing treatments.
Evidence has been accumulating for glutamate disruption in both schizophrenia and autism; accordingly, pre-clinical models are being developed around NMDA receptor (NMDAR) disruption to examine both diseases. NMDA disruption models have been used for many behavioral tasks, but only a few possible electrophysiological endophenotypes such as ERP amplitudes have been investigated. Investigating pre-clinical models of established clinical endophenotypes could lead to better translational biomarkers of disease symptoms.
This thesis's unifying theme is the study of how glutamate disruption can recreate the electrophysiological endophenotypes present in autism and schizophrenia and develop their use as translational biomarkers in both diseases. The primary models of focus are acute NMDA antagonist administration and NMDAR knockdown of PV interneurons. I used these models to examine the relationship between dose and EEG changes, along with the perturbations present with NMDAR disruption in PV interneurons. I investigated the degree to which NMDAR antagonists recreate signal-to-noise ratio (SNR) and timing perturbations in schizophrenia, and found a dose-dependent decrease in SNR and timing consistency. I assessed the extent to which low dose NMDAR antagonism recreates latency and gamma synchrony perturbations present in autism and found latency was increased and gamma synchrony was decreased dose-dependently. I examined the extent to which Parvalbumin (PV) containing interneurons cell type selective NR1 KO mice recreate the clinical EEG profiles of autism and found selective deficits in social behavior and increases in N1 latency.
Saunders IV, John A., "NMDA Receptor Dysfunction and Development of Translational Biomarkers for Autism and Schizophrenia" (2012). Publicly Accessible Penn Dissertations. 574.