Inducing Schizophrenia-like Symptoms in Rats
Dr. Leah Chase, Hope College
Dr. Christopher Barney, Hope College
Dr. John Shaughnessy, Hope College
The hypo-NMDA receptor function hypothesis for schizophrenia is a model that is currently receiving considerable attention. This hypothesis states that decreased NMDA receptor activity in GABAergic interneurons leads to disinhibition of multiple neuronal pathways within the central nervous system, including the corticolimbic pathway. If NMDA receptor function on inhibitory neurons (GABAergic) diminishes, this leads to decreased GABA release and improper signaling in downstream neurons. This process is proposed to lead to the behaviors associated with schizophrenia. The primary objective of this pilot research project was to determine if ablation of GABAergic interneurons (via bilateral intracerebroventricular (i.c.v.) injection of the neurotoxin and NMDA receptor agonist homocysteic acid) in the brain of rats leads to a schizophrenia-like phenotype. To test this hypothesis, ten Sprague Dawley rats were injected with HCA (6 mg) in each lateral ventricle and ten rats were injected with the same volume of CSF in both ventricles. Following injection, the rats were assessed for their spatial learning ability (Morris Water Maze), motor function (rotorod), hedonistic-like/reward-seeking behavior (saccharine preference test), risk-taking behavior (open field test and elevated plus maze), and social behavior (social interaction test) several times over the course of 5 months. We have demonstrated that HCA treatment leads to changes in social interaction such that the HCA treated animals spend more time interacting with the same rat that has been introduced several times compared to control rats. In addition, HCA treatment leads to a reduction in pleasure-seeking behavior, specifically HCA-treated animals drink less sucrose solution than control rats. Finally, HCA rats fall off the rotorod more frequently than control rats. These behaviors are consistent with a schizophrenia phenotype demonstrated in NMDA-receptor knock-down mice. Since HCA is endogenous within the brain, these data suggest further studies of its effect on behavior should be completed.
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