Date of Award

5-26-2021

Document Type

Doctoral Dissertation - Restricted (NYMC/Touro only) Access

Degree Name

Doctor of Philosophy

Department

Cell Biology

First Advisor

Patric K. Stanton

Second Advisor

Libor Velisek

Third Advisor

Jon Horvitz

Abstract

Schizophrenia (SCZ) is a debilitating and economically exhausting mental disorder. In order to further elucidate pathological mechanisms responsible for the disease and identify novel biological targets, we established a new animal model which targets the N-methyl-D-aspartate receptor (NMDAR) subtype of glutamate receptors that are critical for learning and memory-associated activity-dependent synaptic plasticity. Our paradigm can be categorized under the “two-hit” hypothesis of SCZ, which focuses on multiple contributing factors and theorizes the disease develops following a triggering event. The “first hit” disrupts the brain and promotes a vulnerability upon the individual when a stressor later in life, the “second hit”, induces the disease state in susceptible individuals. We administered the psychotomimetic NMDAR antagonist phencyclidine (PCP) during neonatal life (the “first hit”), followed in adolescence by a “second hit”, restraint stress and forced swimming, followed by isolation stress. Neonatal PCP in combination with adolescent stress resulted in cognitive and social deficits, as well as impairment in sensorimotor gating. These animals also showed marked reduction in long-term potentiation of synaptic transmission at hippocampal and medial prefrontal cortical synapses. Finally, we demonstrated the two-hit model’s impairment in synaptic functioning is likely due to an increase in the AMPAR/NMDAR current ratio, produced by a reduction in NMDAR currents resulting from a selective decrease in contribution of NMDAR containing NR2B subunits. These data suggest that our novel two-hit model is associated with persistent positive, negative, and cognitive symptoms of SCZ, and that the development of these symptoms involves, in part, alterations in NMDAR function.

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