Impact of PTEN Loss in Amygdala on Anxiety and Autism Behaviors

A recent study conducted by researchers at the Max Planck Florida Institute for Neuroscience has revealed significant insights into the role of the PTEN gene in the amygdala, particularly concerning anxiety and autism spectrum disorder (ASD) behaviors. Published in the *Frontiers in Cellular Neuroscience* on June 27, 2025, the research elucidates how the loss of PTEN in specific neuronal populations results in structural and functional changes within brain circuits, which in turn heighten anxiety and fear responses in animal models.

The PTEN gene is increasingly recognized as a critical factor associated with autism, particularly in individuals exhibiting macrocephaly, a condition characterized by an unusually large head size. Variations in the PTEN gene have been identified in a notable percentage of individuals with autism, suggesting its pivotal role in neurodevelopmental processes. According to Dr. McLean Bolton, research group leader at the Max Planck Florida Institute, "Understanding these mechanisms is a crucial step toward targeted interventions for specific traits such as severe anxiety."

The researchers focused on the amygdala, a brain region central to emotion regulation and fear responses. They employed a genetic model to specifically disrupt PTEN in somatostatin-expressing inhibitory neurons. This approach allowed them to investigate the localized effects of PTEN loss on neural circuits. The study found that such genetic modifications led to a 50% reduction in local inhibitory connectivity within the central lateral amygdala (CeL), alongside an increased strength of excitatory inputs from the basolateral amygdala (BLA).

Dr. Tim Holford, a prominent member of the research team, highlighted the significance of these findings, stating, "This is a powerful method that we can use to determine changes in local neuron connectivity and strength resulting from genetic variations. We were interested in uncovering how the disruption of PTEN signaling in a single cell type would change the way the brain processes information."

Behavioral assessments indicated that the neuronal alterations correlated with enhanced anxiety and fear learning, while social behaviors remained largely unaffected. This suggests that the anxiety and fear responses associated with PTEN dysfunction may arise from specific microcircuit changes rather than alterations in broader social cognition.

The implications of these findings extend beyond basic neuroscience; they offer a pathway for developing targeted therapies aimed at mitigating anxiety and fear responses in individuals with ASD. As the research team plans to explore these circuits in various genetic models moving forward, their findings underscore the importance of understanding how genetic risk factors operate within distinct neural circuits.

Overall, this study marks a significant advancement in understanding the neurobiological underpinnings of anxiety and autism, indicating that specific genetic expressions can have profound effects on behavior and neural circuitry. Future research may further clarify the potential for targeted interventions that could improve the quality of life for individuals affected by these conditions.

Reference: Holford TW, Letourneau KN, Von-Walter C, Moncaleano D, Loomis CL, Bolton MM. PTEN in somatostatin neurons regulates fear and anxiety and is required for inhibitory synaptic connectivity within central amygdala. *Front Cell Neurosci*. 2025;19:1597131. doi: 10.3389/fncel.2025.1597131.