Abstract
Cognitive symptoms are core features of mental disorders but procognitive treatments are limited. We have proposed a “discoordination” hypothesis that cognitive impairment results from aberrant coordination of neural activity. We reported that neonatal ventral hippocampus lesion (NVHL) rats, an established neurodevelopmental model of schizophrenia, have abnormal neural synchrony and cognitive deficits in the active place avoidance task. During stillness, we observed that cortical local field potentials sometimes resembled epileptiform spike-wave discharges with higher prevalence in NVHL rats, indicating abnormal neural synchrony due perhaps to imbalanced excitation–inhibition coupling. Here, within the context of the hypothesis, we investigated whether attenuating abnormal neural synchrony will improve cognition in NVHL rats. We report that: (1) inter-hippocampal synchrony in the theta and beta bands is correlated with active place avoidance performance; (2) the anticonvulsant ethosuximide attenuated the abnormal spike-wave activity, improved cognitive control, and reduced hyperlocomotion; (3) ethosuximide not only normalized the task-associated theta and beta synchrony between the two hippocampi but also increased synchrony between the medial prefrontal cortex and hippocampus above control levels; (4) the antipsychotic olanzapine was less effective at improving cognitive control and normalizing place avoidance-related inter-hippocampal neural synchrony, although it reduced hyperactivity; and (5) olanzapine caused an abnormal pattern of frequency-independent increases in neural synchrony, in both NVHL and control rats. These data suggest that normalizing aberrant neural synchrony can be beneficial and that drugs targeting the pathophysiology of abnormally coordinated neural activities may be a promising theoretical framework and strategy for developing treatments that improve cognition in neurodevelopmental disorders such as schizophrenia.
Highlights
Cognitive impairment is a core feature of schizophrenia but treatments to improve cognition are limited, in part because the physiological mechanisms of cognitive dysfunction are unclear
The main finding of this study is that a drug that normalizes aberrant cognition-related neural synchrony in neonatal ventral hippocampus lesion (NVHL) rats can attenuate the cognitive control impairment in this schizophreniarelated neurodevelopmental model of mental dysfunction
The findings reported here are consistent with the main assertion and prediction of the discoordination hypothesis that abnormal neural synchrony during cognitive effort is associated with impaired cognition and that restoring normal synchrony will promote cognition
Summary
Cognitive impairment is a core feature of schizophrenia but treatments to improve cognition are limited, in part because the physiological mechanisms of cognitive dysfunction are unclear. Treatments that normalize neural network dysfunction without addressing the underlying cellular pathology have been sufficient to improve cognitive function in animal models of neurodegenerative diseases [14, 15]. Such studies demonstrate it may be a feasible strategy to improve cognitive functional outcomes by normalizing aberrant neural network synchrony in cases where the network dysfunction is part of the causal chain from the disease etiology to the manifest cognitive symptoms
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