Excitation/Inhibition Balance & Cognition in Schizophrenia: Building a Multi-Scale Understanding

Cognitive symptoms of schizophrenia account for a significant proportion of the disease’s morbidity but have no effective pharmacological treatments.

Cognition involves coordinated patterns of activity in functional brain networks, which in turn depend on interactions between excitatory glutamatergic pyramidal cells and inhibitory GABAergic interneurons.

Perturbation of the excitatory and inhibitory (E/I) balance may underlie disruption of the functional networks in schizophrenia, and therefore result in cognitive impairments.

Normalisation of this putative E/I imbalance represents a promising therapeutic target for novel treatments of schizophrenia, particularly those intended to improve cognition.

A major obstacle to investigating these hypotheses is the lack of methods to derive mesoscale measures of E/I imbalance from observable macroscale measures of functional networks in patients.

I will develop a novel cross-species biomarker of E/I balance, derived from computational modelling of functional MRI and EEG. I will validate the approach using a mouse model in which the true microcircuit nature of E/I dysfunction is known.

I will then use this method to characterise E/I balance in individuals with schizophrenia and determine possible connections with cognitive impairments.

Finally, I will use the approach to elucidate whether memantine, a potential treatment for cognitive deficits in schizophrenia, acts by restoring E/I balance.