Abstracts

Rationale: Clinical data show comorbidity of epilepsy with a number of psychosis syndromes, including postictal, interictal and periictal psychoses and schizophrenia. However, the pathophysiology of psychosis and of its linkage to epilepsy has remained obscure. Because abnormal neural synchronization at a macro neural scale is established in epilepsy and more subtle abnormalities in neural synchrony at a micro neural scale are observed in schizophrenia, we hypothesized a failure of coordination in the timing of action potentials within and between specific networks of neurons as a pathophysiological mechanism that associates epilepsy and psychosis. We have begun to test this hypothesis, initially by looking for signs of epilepsy in an animal model with well-established features of psychosis. Methods: The excitotoxin Ibotenic acid (IBO; 10 μg/μl) or saline was injected bilaterally near the ventral hippocampus of male Long-Evans rats on postnatal day 7 (PD7). Behavioral and cognitive tests and local field potential (LFP) recordings (0.1-500 Hz) were performed when the rats were adult (PD>56). Locomotor activity, habituation to novelty, and prepulse inhibition of the auditory startle reflex were assessed as standard indicators for animal models of psychosis. Since cognitive control deficits are now recognized as a core feature of schizophrenia, we also assessed cognitive control using a novel two-frame active place avoidance task. The task requires a rat on a slowly-rotating arena to segregate stationary room cues from irrelevant, rotating-arena cues that must be ignored in order to avoid a stationary shock zone. Rats were implanted with 75-µm electrodes in up to 16 sites for digital video-synchronized recordings. Recording targets included the piriform cortex, amygdala, entorhinal cortex, thalamus, medial prefrontal cortex, dorsal and ventral hippocampus. A skull-screw was used for epidural cortical recordings. Head-mounted amplifiers minimized noise and artifact. Wideband (0.1-6000 Hz) signals were transmitted either by wires or wirelessly by digital radio to permit continuous monitoring. Results: IBO-treated rats (IBO rats) were compared to their saline-treated littermates. Adult IBO rats expressed the standard behavioral abnormalities that were previously linked to psychosis. The IBO rats also had a cognitive control deficit that is a central feature of schizophrenia. Remarkably, the IBO rats exhibited sporadic, spontaneous, recurrent behavioral and electrographic seizures that have not previously been reported in an animal model exhibiting features of psychosis. Generalized seizures were detected in ~30% of IBO animals, but seizures may be more prevalent because continuous monitoring has not yet been conducted. Conclusions: The results support the hypothesis that aberrant neural coordination underlies both epilepsy and its associated psychoses. The IBO model, and advances in recording both macro scale field potentials and micro scale action potentials may help elucidate the neural mechanisms that associate epilepsy and psychosis, and permit continuous monitoring that may reveal previously unnoticed seizures in other animal models.