Title: Excitation/Inhibition Balance in Autism Spectrum Disorder and Schizophrenia: Building A Multi-Scale Understanding
Funder: The Academy of Medical Sciences

Abstract: We aim to determine whether the genetic architecture of excitation/inhibition (E/I) balance overlaps with that of schizophrenia and autism spectrum disorder (ASD), and whether genes associated with E/I balance are enriched for specific biological pathways. In addition, we will characterise the effects of the drug riluzole on E/I balance in ASD and schizophrenia in greater detail. Normal cognitive function is associated with coordinated patterns of brain activity. These patterns are termed functional networks. Schizophrenia and ASD are neurodevelopmental disorders associated with aberrant functional networks, and these differences are linked to symptoms. A key question is therefore what are the molecular underpinnings of these differences in functional networks? A candidate system for this is the delicate balance between excitatory glutamatergic neurons and inhibitory GABAergic neurons. This E/I balance is associated with functional network architecture, and post-mortem and preclinical work suggest that E/I balance is disrupted in both schizophrenia and ASD. Our preliminary results show that the drug riluzole, a drug that modulates both GABAergic and glutamatergic function, is able to shift neuroimaging markers of glutamate in schizophrenia and ASD. We found that this shift is associated with changes in functional networks, thereby demonstrating a neuroimaging based biophysical signature of E/I balance. We now intend to leverage this result and investigate genetic associations with neuroimaging markers of E/I balance in over 30,000 individuals. The results of this study have the potential to identify new targets for pharmacological intervention with clear mechanistic links to the underlying neurobiology.

Lay abstract: The human brain is composed of billions of nerve cells which communicate by exciting and inhibiting one another. This delicate balance between excitation and inhibition (E/I balance) gives rise to patterns of larger scale brain activity, called functional networks, that we can observe using brain scans. Post mortem and animal studies suggest that E/I balance is disrupted in schizophrenia and autism spectrum disorder (ASD). Meanwhile brain scans have shown that these illnesses also show disrupted functional networks. Aberrant E/I balance may therefore lead to disrupted functional networks, which in turn may underlie the symptoms of schizophrenia and ASD. A drug called riluzole alters levels of glutamate, a chemical central to maintaining E/I balance. We found that giving riluzole to individuals with schizophrenia and ASD shifts glutamate markers, and that this is associated with changes in functional networks. This demonstrates that we can assess E/I balance with brain scans. In the current study we intend to assess the molecular and genetic underpinnings of E/I balance by measuring functional networks in over 30,000 individuals who have received both brain scans and had their DNA sequenced. This will allow us to see if the genes associated with E/I balance are similar to the genes associated with schizophrenia and autism. We will look at what biological pathways these genes are involved in, and also look at precisely how riluzole affects E/I balance. Together this will give us clues as to how to develop new medicines, or use existing ones to treat ASD and schizophrenia.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH