Neural discoordination: A pathophysiological mechanism of cognitive dysfunction in a neurodevelopmental animal model of schizophrenia.

Abstract

Cognitive impairments are the best determinants of functional outcome in schizophrenia but there is currently no effective procognitive treatment available. Efforts to improve cognition in schizophrenia are limited, in part because the mechanisms of the cognitive deficits are unclear. The discoordination hypothesis postulates that the underlying pathophysiological mechanism of the cognitive deficits is the aberrant coordination of neural activity within and between the neural networks that subserve cognition. We examined the discoordination hypothesis in the neonatal ventral hippocampal lesion (NVHL) rats, an established neurodevelopmental animal model of schizophrenia. To study the association between abnormal neural synchrony and cognitive impairment in NVHL rats, we recorded local field potentials and assessed cognitive control using the two-frame place avoidance task. Local field potentials were recorded from the hippocampus and the prefrontal cortex. Adult NVHL rats were impaired in performing the two-frame task compared to the control rats. The decreased inter-hippocampal synchrony in the NVHL rats also correlated with their poor performance in the two-frame task. We evaluated therapeutic options to improve cognitive performance in the NVHL rats by targeting abnormal synchrony. We first examined the effects of early intervention by giving cognitive training at adolescent period (P35). Adolescent NVHL and control rats learned the two-frame task without any difficulty. Adolescent cognitive training prevented adult cognitive control impairment in adult NVHL rats, and the benefit generalized to different tasks such as alternation T-maze task and the conflict avoidance task. Adult NVHL rats that had received adolescent cognitive training had increased inter-hippocampal synchrony while performing the two-frame task and this increase in synchrony was normalized to the level of the control rats. This again demonstrates that improved performance in the two-maze task correlated with increased inter-hippocampal synchrony in NVHL rats. We also examined the effects of olanzapine and ethosuxmide drug treatments in adult NVHL rats. Both olanzapine and ethosuximide treatments hypersynchronized the inter-hippocampal and the inter-hippocampus-prefrontal networks but only ethosuxmide treatment increased inter-prefrontal synchrony in NVHL rats. We have established a direct association between abnormal neural synchrony and cognitive control impairment in the NVHL rats by demonstrating the following: 1) NVHL rats have decreased long-range inter-hippocampal synchrony that correlates with poor cognitive control performance in the two-frame task; 2) early cognitive training prevents adult cognitive control impairment and normalizes the long-range inter-hippocampal synchrony to the level of the control rats; 3) targeting synchrony with drug treatments can change cognitive performance levels in the adult NVHL rats. These data demonstrate that targeting synchrony abnormality can offer tremendous promise for improving intellectual competence in people at risk for schizophrenia.