Reactivating Critical Periods of Brain Development

Background: Neural circuits are shaped by genes and environment during early windows of brain development. Recent work with classic models of deprivation amblyopia in animals has begun to unravel the cellular and molecular constraints that establish such ‘critical’ or ‘sensitive’ periods for plasticity. Of particular clinical relevance is the extent to which a critical period can be safely and non-invasively recapitulated.

Objectives: This talk will summarize mechanistic insight into the opening, execution and closure of circuit rewiring in the neocortex of mice. The aim is to establish key principles across systems and their relevance to autism spectrum disorders.

Methods: We focused on the pivotal role for late developing excitatory-inhibitory (E/I) circuit balance in the initiation of critical periods. Genetic disruption of GABA synthesis or the maturational state of parvalbumin (PV)-positive basket cells delays onset, while benzodiazepines or treatments that accelerate PV-circuit maturation trigger premature plasticity. Once induced, synaptic rewiring in response to monocular deprivation or tone-rearing is manifest by increased dendritic spine motility and pruning followed by regrowth. Moreover, inputs onto inhibitory PV-cells exhibit a dynamic bidirectional plasticity. These changes are ultimately hard-wired as part of the large-scale connectivity of afferent axons by the end of the critical period.

Results: Plasticity gradually winds down as a consequence of late-appearing molecular factors with a characteristic duration proportional to species’ lifespan. Effects of early visual experience or deprivation are thus actively maintained throughout life. Two such classes of molecular “brakes” on plasticity have been identified: those that limit structural change and those that regulate E/I balance. Axonal growth inhibitors include myelin related proteins (NgR, PirB) or chondroitin sulphate proteoglycans forming tight peri-neuronal nets (PNNs) around mature PV-basket cells. Regulators of E/I balance include neuromodulators, such as serotonin and acetylcholine. Manipulation of any of these “brakes” enables the reactivation of visual cortical plasticity and recovery from amblyopia in adulthood.

Conclusions: The biology of the brain is heavily invested in the optimal timing and duration of plasticity, having evolved numerous molecular checks and balances. Notably, many of these cellular players are associated with critical period profile across systems, and may go awry in the etiology of developmental disorders, such as autism.