An Early Enriched Experience Drives an Activated Microglial Profile at Site of Corrective Neuroplasticity in Ten-m3 Knock-Out Mice

Environmental enrichment (EE) is beneficial for brain development and function, but our understanding of its capacity to drive circuit repair, the underlying mechanisms, and how this might vary with age remains limited. Ten-m3 knock-out (KO) mice exhibit a dramatic and stereotyped mistargeting of ipsilateral retinal inputs to the thalamus, resulting in visual deficits. We have recently shown a previously unexpected capacity for EE during early postnatal life (from birth for six weeks) to drive the partial elimination of miswired axonal projections, along with a recovery of visually mediated behavior, but the timeline of this repair was unclear. Here, we reveal that with just 3.5 weeks of EE from birth, Ten-m3 KOs exhibit a partial behavioral rescue, accompanied by pruning of the most profoundly miswired reti-nogeniculate terminals. Analysis suggests that the pruning is underway at this time point, providing an ideal opportu-nity to probe potential mechanisms. With the shorter EE-period, we found a localized increase in microglial density and activation profile within the identified geniculate region where corrective pruning was observed. No comparable response to EE was found in age-matched wild-type (WT) mice. These findings identify microglia as a potential mechanistic link through which EE drives the elimination of miswired neural circuits during early postnatal develop-ment. Activity driven, atypical recruitment of microglia to prune aberrant connectivity and restore function may have important therapeutic implications for neurodevelopmental disorders such as autistic spectrum disorder.