A groundbreaking study led by investigators affiliated with BBRF has shed light on why psychosis often emerges during adolescence and is associated with specific changes in brain activity, particularly within the hippocampus. The research team, headed by Dr. Carol A. Tamminga, a prominent member of the BBRF Scientific Council, has developed a mouse model that mimics behaviors seen in schizophrenia patients, focusing on the role of the hippocampus. Their findings suggest that abnormalities in this brain region may be crucial in understanding the onset of psychosis, especially during the critical period of adolescence.
Hippocampal Hyperactivity and Its Link to Psychosis
The research highlights the importance of the hippocampus, a brain structure involved in memory and learning, in the development of psychosis. Previous studies have shown that reduced expression of a protein called GluN1 in the dentate gyrus—a part of the hippocampus—correlates with increased activity in other hippocampal regions. This hyperactivity is thought to contribute to symptoms like hallucinations and delusions. The team's work builds on these observations by exploring how such changes might occur and their timing relative to behavioral alterations.
To delve deeper into this phenomenon, the researchers used a genetically engineered mouse model where the gene responsible for producing GluN1 was selectively "knocked out" in the dentate gyrus. This manipulation led to decreased excitatory activity in the dentate gyrus but increased activity in other parts of the hippocampus, resulting in behaviors reminiscent of psychosis. Further experiments revealed that acute activation of neurons specifically in the CA3 layer of the hippocampus also induced similar behaviors. These findings suggest that hyperactivity in the CA3 region alone could be sufficient to trigger psychosis-like symptoms. Importantly, the team discovered that these effects were more pronounced when the suppression of GluN1 occurred during adolescence rather than adulthood, indicating a heightened vulnerability during this developmental stage.
Adolescent Sensitivity and Persistent Effects of Hippocampal Dysfunction
The study also uncovered two significant behavioral deficits in adolescent mice following hippocampal hyperactivity: impaired social cognition and spatial working memory. Both of these issues are commonly observed in individuals experiencing psychosis. The researchers noted that the emergence of hyper-synchronous events (HSEs)—distinct bursts of cellular activity throughout the hippocampus—was mechanistically linked to these behavioral changes. These HSEs began to appear two weeks after the inhibition of the dentate gyrus and persisted even after the experimental intervention ended, suggesting long-lasting or permanent effects.
The timing of these changes provides valuable insights into the progression of hippocampal dysfunction. While the initial inhibition of the dentate gyrus lasted three weeks, the subsequent hyperactivity and behavioral deficits continued for an extended period, emphasizing the potential for lasting impact. The research underscores the unique sensitivity of the adolescent brain to such disruptions, offering a possible explanation for why psychosis typically manifests during this critical developmental window. By identifying the mechanisms underlying hippocampal hyperactivity, this study paves the way for better understanding and potentially treating psychosis in young individuals.
