Excessive excitation can become toxic to neurons and contribute to alterations in certain brain regions that are particularly vulnerable and involved in psychosis, such as the hippocampus
Alessandro Pascucci
The UNIGE research team focused on 22q11.2 deletion syndrome, a genetic condition associated with a 30-40% risk of developing psychotic symptoms. This microdeletion includes genes involved in the integrity of the glymphatic system, which acts as a brain waste-clearance system. It eliminates metabolic waste, inflammatory molecules, and excess neurotransmitters through the circulation of cerebrospinal fluid and its exchanges with the interstitial fluid that surrounds brain cells. This cerebral drainage system may promote inflammation and neuronal toxicity when it is not functioning properly. Both of these phenomena are suspected of promoting the onset of psychotic symptoms.
The team analysed a cohort of individuals with 22q11.2 deletion syndrome who were followed from childhood to adulthood and compared them to healthy individuals. Longitudinal imaging data, that were first collected more than twenty-five years ago, were reanalysed using new techniques that were optimised and automated by the team. Within the 22q11.2 group, a subgroup developed psychotic symptoms during follow-up, allowing the identification of distinct neurodevelopmental trajectories. Using a specific methodology applied to a diffusion magnetic resonance imaging technique — which measures the diffusion of water molecules in the brain — the team was able to indirectly estimate glymphatic system function.
The researchers thus observed that the brain’s clearance system was significantly altered in individuals carrying the 22q11.2 deletion, and already in childhood. Moreover, while glymphatic system efficiency normally increases during development, this progression was not observed in a subgroup of participants with the 22q11.2 deletion who developed psychotic symptoms. “This atypical trajectory suggests that a vulnerability resulting from an interaction between biological and environmental factors is present well before the onset of symptoms,” explains Alessandro Pascucci, first author of the study, PhD student in the Department of Psychiatry at the Faculty of Medicine and at the Synapsy Center at UNIGE, and resident doctor in child psychiatry at the Fondation Pôle Autisme.
The researchers also measured the balance between excitatory and inhibitory signals in the hippocampus by studying two types of neurotransmitters: glutamate, which stimulates neuronal activity, and GABA, which inhibits it. The lower the efficiency of the brain’s clearance system, the more pronounced this imbalance was. “Excessive excitation can become toxic to neurons and contribute to alterations in certain brain regions that are particularly vulnerable and involved in psychosis, such as the hippocampus. Our results suggest a link between glymphatic system dysfunction, mechanisms of neurotoxicity, and psychosis,” says the clinician-researcher.
These results suggest that an impaired glymphatic system could make the brain more vulnerable to the onset of psychosis, possibly through inflammation or excessive neuronal excitation. The next steps will be to analyse the links between peripheral inflammation, observable in the blood, sleep quality, which is known to influence glymphatic function, and the onset of psychosis. “Identifying such modifiable predictive factors could pave the way for strategies to delay or even prevent a first psychotic episode,” concludes Stephan Eliez, full professor in the Department of Psychiatry at the Faculty of Medicine and at the Synapsy Center at UNIGE, and director of the Pôle Autisme Foundation.
Source: University of Geneva