A CORRELATED BEHAVIORAL AND BIOCHEMICAL ANALYSIS INVESTIGATING GONADAL INFLUENCE ON PREFRONTAL CORTICAL FUNCTION THROUGH MODULATION OF NMDA RECEPTOR TRAFFICKING

Abstract

Neuronal activity in the prefrontal cortex (PFC) underlies working memory processes in the brain. Reports have suggested critical roles for gonadal steroid modulation of this PFC function in adult male rats (Kritzer et al 2007), yet the exact mechanisms have yet to be defined. Given the clinical implications of male PFC vulnerability with schizophrenia, this is an important question to be addressed. This thesis seeks to gain insight as to whether hormone control over NMDA-receptor mediated glutamate signaling may be part of the way hormones influence the PFC's complex operations. This will be accomplished in interrelated studies using gonadally intact control and gonadectomized male rats. First, Barnes Maze behavioral testing for spatial working memory recently shown to be impaired in gonadectomized (GDX) rats, will be used to determine whether a behavioral rescue in subjects can be ascertained by locally blocking NMDA receptors using (2R)-amino-5-phosphonopentanoate (APV, an NMDA antagonist) within the PFC. Complementary studies will evaluate the subcellular distribution profiles for the NR1 subunit of the NMDA receptor in PFC of control (SHAM) and GDX rats. In both studies, overexpression/overactivity of NMDA receptors at PFC synapses is expected in GDX relative to control rats. To date, the data collected indeed support the hypotheses that reduction of NMDA over-activity via APV in GDX restores PFC-dependent behaviors depicted by an enrichment of NR1 proteins at the membrane and at synapses in GDX PFC relative to controls.