Rodriguez Sanchez, Julia; (2024) Computational modelling of excitatory and inhibitory cell function in psychosis spectrum disorders. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The glutamatergic synapse has emerged as a potential target for antipsychotic drug development over the past three decades, based on the hypothesis that dysregulation of glutamatergic transmission, particularly involving N-methyl-d-aspartate (NMDA) receptors, plays a central role in the pathophysiology of schizophrenia. However, it remains unclear which cell types are primarily affected, and whether different patients may benefit from different treatments. This thesis addresses these questions by investigating the role of excitatory pyramidal cells and inhibitory interneurons in the emergence of psychosis. The first chapter provides a review of excitation and inhibition in schizophrenia, and discusses the need for a more detailed understanding of excitatory/inhibitory balance. Subsequent chapters examine excitatory and inhibitory cell function in individuals at clinical high risk for psychosis (CHR-P) using dynamic causal modelling and three magneto- and electroencephalography (M/EEG) paradigms. Chapters 2 and 3 focus on modelling passive and active auditory oddball EEG data from 580 CHR-P and 240 healthy control participants from the North American Prodrome Longitudinal Study 2. They show that observed EEG deficits are primarily explained by pyramidal cell dysfunction, and provide evidence that disinhibition within cortical circuits is associated with symptom severity and the emergence of psychosis. Chapter 4 extends these findings using a conductance-based model with explicitly parameterised glutamatergic and GABAergic receptors. This model is applied to 40 Hz auditory steady-state MEG data from 116 CHR-P participants, 49 participants with first-episode psychosis and 49 healthy controls, providing further evidence of pyramidal cell dysfunction – attributable, at least in part, to hypofunction of NMDA receptors – in CHR-P and first-episode groups. These findings demonstrate that both excitatory and inhibitory cell function are already altered in the early stages of psychosis, and underscore the potential of targeting glutamatergic signalling to improve symptoms.

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