Neocortical excitation/inhibition balance in information processing and social dysfunction

Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30–80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms. Brain imbalance in autism One model for the cellular disturbances underlying social and emotional deficits in disorders such as autism and schizophrenia is an imbalance in excitatory and inhibitory activity in certain neural systems. This idea has not been directly testable so far, but testability comes a little closer with the development of two optogenetic tools that have different spectral and temporal characteristics, thereby allowing selective control of two intermingled populations of neurons. Use of these new opsins shows that increasing relative excitation in mouse prefrontal cortex impairs social and learning behaviours. This provides support for the elevated cellular excitatory/inhibitory balance hypothesis of certain neuropsychiatric symptoms.