Microglia: Mediators of experience-driven corrective neuroplasticity

Neural connectivity is essential for brain function: this is initially established via early axon guidance mechanisms and subsequently refined by synaptic pruning. Alterations in the patterns of neural connectivity, arising due to changes in either of these processes, are found in neurodevelopmental conditions. Microglia, the brain's resident immune cell, are recognised mediators of synaptic pruning. Unlike axon guidance, synaptic pruning occurs over protracted periods of postnatal life and can be profoundly impacted by experience. Little is known about whether targeted microglial synaptic pruning could be recruited to compensate for alterations in neural connectivity arising due to deleterious changes in other neurodevelopmental processes, such as axon guidance. Here we review our recent work which has addressed this by examining the effect of Environmental Enrichment (EE) on the miswired visual circuitry of mice lacking the axon guidance molecule Ten-m3. Notably, exposure to EE commenced around birth (but not from weaning or later) triggered selective removal of miswired retinal inputs in the visual thalamus of these Ten-m3 knockout mice. Most importantly, our work identifies selective microglial engulfment of neural connections during a defined postnatal window, as a likely mediator of this effect of early EE. The findings reviewed here emphasise the importance of early life experience in shaping neural circuitry, particularly when early development has been compromised by genetic factors. They also provide a potential mechanistic underpinning for the results of recent clinical trials investigating the effectiveness of early, experience-based interventions for human neurodevelopmental conditions.