Scientists at the Institute for Neurosciences, led by Juan Lerma, have uncovered a specific neural mechanism in the amygdala that drives anxiety, depression, and social withdrawal, with striking implications for future treatments. Published recently in iScience, the study demonstrates that correcting an imbalance in excitability within a precise subset of neurons can reverse these pathological behaviors in mice, illuminating a targeted pathway for addressing mood disorders.
The amygdala, central to emotion processing, contains multiple neuronal populations contributing to complex behaviors. Lerma’s team focused on the basolateral amygdala, where genetically modified mice overexpressing the Grik4 gene exhibit increased GluK4 glutamate receptor levels, heightening neuronal excitability. These mice displayed pronounced anxiety and social deficits analogous to human psychiatric conditions like autism and schizophrenia.
Using advanced genetic engineering and viral vector delivery, the researchers selectively normalized Grik4 expression in basolateral amygdala pyramidal neurons. This recalibration restored normal communication with inhibitory “regular firing neurons” located in the centrolateral amygdala. Electrophysiological recordings confirmed the reestablishment of synaptic balance, while behavioral assays—including tests for anxiety, depression, and social interaction—showed significant reversal of deficits. For example, affected mice regained interest in open spaces and social novelty.
Importantly, applying this approach to wild-type mice exhibiting natural anxiety further validated the findings, indicating the mechanism’s broader applicability beyond engineered models. While anxiety and social withdrawal symptoms improved, cognitive impairments such as object recognition memory remained, suggesting other brain areas like the hippocampus are involved in these functions.
Lead author Álvaro García emphasized that restoring excitability balance in specific amygdala circuits could revolutionize treatment strategies by offering more localized, efficient interventions for mood and social behavior disorders. This work lays the groundwork for future therapies targeting neural circuit dysfunctions underlying affective illnesses, potentially transforming clinical approaches to anxiety and depression.
REFERENCE: Alvaro García, M. Isabel Aller, Ana V. Paternain, Juan Lerma. Central role of regular firing neurons of centrolateral amygdala in affective behaviors. iScience, 2025; 28 (6): 112649 DOI: 10.1016/j.isci.2025.112649
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