Adolescent Circuit Remodeling: How Microglia Shape the Frontal Cortex and Mental Health?

A very sensitive period for the functional and structural development of the frontal cortex is the adolescent period.¹ During adolescence, the brain's frontal cortex responsible for critical executive functions like planning a smoothie, choosing to go for a walk, or understanding another’s feelings, undergoes dramatic maturation. If these developing circuits don’t properly refine, the risk of neurodevelopmental disorders such as schizophrenia and ADHD increases. Researchers at the Del Monte Institute for Neuroscience, University of Rochester, have now uncovered a vital role for microglia, the brain’s resident immune cells, in guiding this adolescent plasticity. Their findings, published in Nature Communications, may open new therapeutic avenues targeting these cells during adolescence and beyond.²

Using live imaging in adolescent mice, scientists demonstrated that rewarding stimuli, such as running, stimulate the frontal dopaminergic (DA) pathway, prompting microglia to increase their surveillance of DA axons and engage in contact events. Intriguingly, these microglial contacts preceded the emergence of new synaptic boutons along DA axons, the crucial structures for neurotransmitter release, suggesting a microglial guidance role in synaptic strengthening.³

At the molecular level, the study showed that dopamine receptor signaling strongly influences microglial responses. Specifically, activation of dopamine D2 receptors in adolescent mice inhibited microglial surveillance and blocked bouton formation, while in adult mice, antagonizing D2 receptors (using eticlopride) reinstated both microglial recruitment and bouton growth, effectively recapitulating adolescent-like plasticity in the mature brain.

The researchers also identified microglial purinergic receptor P2RY12 as indispensable for activity-driven plasticity. Blocking P2RY12 signalling prevented both sustained post-stimulation microglial process extension and subsequent bouton formation, underscoring its necessity in the microglia-mediated remodelling of DA circuits.

Together, these results establish a dynamic, bidirectional interaction: dopaminergic activity mobilizes microglial surveillance, and in turn, microglia actively shape the formation of new synaptic connections during adolescence. This positions microglia as critical sculptors of synaptic architecture and offers compelling targets for interventions aiming to restore or enhance frontal cortical plasticity in disorders emerging during adolescence or persisting into adulthood.

Future work will focus on dissecting the precise molecular interactions through which microglia influence bouton formation likely involving targeted pharmacological manipulations and single-cell sequencing to better understand why this plasticity window is so age-specific and how it might be reopened in adults.