Balancing plasticity/stability across brain development.

The potency of the environment to shape brain function changes dramatically across the lifespan. Neural circuits exhibit profound plasticity during early life and are later stabilized. A focus on the cellular and molecular bases of these developmental trajectories has begun to unravel mechanisms, which control the onset and closure of such critical periods. Two important concepts have emerged from the study of critical periods in the visual cortex: (1) excitatory-inhibitory circuit balance is a trigger; and (2) molecular "brakes" limit adult plasticity. The onset of the critical period is determined by the maturation of specific GABA circuits. Targeting these circuits using pharmacological or genetic approaches can trigger premature onset or induce a delay. These manipulations are so powerful that animals of identical chronological age may be at the peak, before, or past their plastic window. Thus, critical period timing per se is plastic. Conversely, one of the outcomes of normal development is to stabilize the neural networks initially sculpted by experience. Rather than being passively lost, the brain's intrinsic potential for plasticity is actively dampened. This is demonstrated by the late expression of brake-like factors, which reversibly limit excessive circuit rewiring beyond a critical period. Interestingly, many of these plasticity regulators are found in the extracellular milieu. Understanding why so many regulators exist, how they interact and, ultimately, how to lift them in noninvasive ways may hold the key to novel therapies and lifelong learning.