Date of Award
Doctoral Dissertation - Restricted (NYMC/Touro only) Access
Doctor of Philosophy
Patric K. Stanton
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.
Moghadam, Alexander, "A novel two-hit, N-methyl-D-aspartate receptor dependent, developmental model of schizophrenia" (2021). NYMC Student Theses and Dissertations. 22.