Homeostatic Plasticity in Psychosis-related Copy Number Variation

Psychosis has been characterised as disorder of aberrant salience, or maladaptive responses to changes in the external environment (Kapur, 2003). This model posits that psychotic symptoms start to appear when disordered dopaminergic transmission leads to the attribution of significance to stimuli that would normally be considered irrelevant. The relationship between this homeostatic deficit in the cognitive phenomenology of psychosis and homeostatic mechanisms of neural networks is not clearly understood, and can be difficult to study in vivo due to the complexity of cortical circuits. The genetic contribution to this regulatory deficit, particularly stemming from copy number genetic variants (deletions or duplications of large (~100kb+) segments of DNA), although robustly linked to psychosis in several instances, is also not mechanistically well defined.

My general hypothesis is that copy number variation (CNV) has a generic and pernicious effect on adaptive neuronal plasticity. This may be important in terms of understanding a variety of psychiatric syndromes (such as schizophrenia) in terms of abnormal gain control and cortical excitability. Aberrant salience and aberrant precision hypotheses of schizophrenia rest on abnormal gain control and its electrophysiological correlates (in particular, attenuated mismatch negativity [MMN] - an electrophysiological proxy for early auditory processing and neuronal plasticity (Baldeweg & Hirsch, 2015). I will therefore investigate this hypothesis using existing genetic and electrophysiological data from patients with psychosis, and address the same question at a synaptic level using cultured neurons induced from iPSCs with 22q11.2 deletions (which is the highest-risk CNV locus for schizophrenia).

The project primarily aims to:

Analyse existing data from a large cohort of subjects in terms of the relationship between CNVs and (attenuated) MMN in psychosis.
To generate cortical neurons from induced pluripotent stem cells (iPSCs) with copy number variants (CNVs) that are associated with an increased risk of psychosis (such as 22q11.2 deletion).
To investigate whether there are distinct cellular phenotypes in iPSC-neurons derived from 22q11.2 patients in response to changes in stimulation or extracellular conditions; i.e. how they respond to variation outside of an "attractor state" (a state of dynamic equilibrium, or least free energy).
Associate these neural network characteristics with cognitive endophenotypes of patients from whom the samples were collected (particularly in dealing with environmental variability & salience.

Techniques used:
- Genome-wide association (bioinformatics)
- Neurophysiology, analysis of EEG and evoked potential data
- Culturing human iPSCs
- Differentiating iPSCs into cortical neurons to generate neuronal networks
- Pharmacological stimulation of neuronal cultures
- Dynamic causal modelling (DCM)