It is increasingly acknowledged that psychotic disorders have a developmental nature, which might have important repercussions on early disease-modifying strategies. Chromosome 22q11.2 deletion syndrome (22q11DS) is a neurogenetic disorders associated with a substantial risk to develop a psychotic disorder by adulthood. Thanks to the early genetic diagnosis, 22q11DS is an ideal model to prospectively study brain changes associated with the risk to develop a psychotic disorder. This dissertation focuses on the exploration of neural circuits potentially affected by derailments from physiological brain maturation processes during critical developmental periods such as adolescence.

The first objective of this thesis was to investigate if the maturation of the hippocampal formation affects the risk to develop psychotic symptoms in deletion carriers. To this aim, we employed brain morphometry, magnetic resonance spectroscopy (MRS) and we estimated the polygenic risk score for schizophrenia (PRS) to explore the influence of other genetic variants outside the locus of the 22q11 deletion. Deletion carriers with psychotic symptoms displayed deviant longitudinal trajectories of hippocampal and related subfields volume during late adolescence. Moreover, a high PRS for schizophrenia was associated with greater hippocampal atrophy in deletion carriers. Finally, elevated levels of glutamate metabolites predicted hippocampal atrophy in psychotic deletion carriers. Overall, these findings support a model of hippocampal pathology characterized by enhanced regional glutamatergic transmission, cellular death via excitotoxicity and atrophy observed at the macroscopic level.

The second aim was to characterize gamma-band oscillations (>30 Hz) as a marker of excitatory/inhibitory balance during sensory processing. Using high-density EEG, we measured gammaband oscillations elicited by the 40 Hz auditory steady-state response (ASSR) task and a visual grating task. We identified a consistent decrease in gamma-band response to both auditory and visual task, as well as a lack of expected age-related increase in gamma-band power as compared to a group of controls. Moreover, deletion carriers with attenuated psychotic symptoms displayed a further reduction in ASSR gamma-band response, combined with a decreased theta-gamma coupling between prefrontal regions and the auditory cortex. Given that gamma-band oscillations arise from the interplay between pyramidal neurons and fast-spiking interneurons, these findings can be interpreted as a disruption of the excitatory/inhibitory balance.

Collectively, these results support the hypothesis that an impaired maturation of the excitatory/inhibitory balance during adolescence in temporo-limbic brain regions might predispose subjects at genetic risk for psychosis to the development of attenuated psychotic symptoms. Therefore, these findings potentially contribute to identifying targets for early intervention in psychotic disorders.