Professor of Molecular and Cellular Biology
Department of Molecular and Cell Biology
(November 3, 2015)
Balancing Plasticity/Stability Across Brain Development
What if autism could be reversed in adulthood? Developmental disorders are often due to disruptions during key developmental periods, called critical periods. Abnormal development during critical periods currently leads to behavioral, functional and cognitive problems down the road. But what if it doesn’t have to be that way? The Hensch lab is examining the molecular processes behind critical periods and methods to reopen them later in life. By reopening a critical period, it may be possible to treat altered brain development or repair damage due to a brain injury.
During development, different brain systems exhibit transient periods of heightened plasticity, referred to as “critical periods,” that allow children to rapidly acquire sensory, motor, cognitive, and language skills. Disruption of these critical periods early in life can have profound developmental consequences. For instance, subtle differences in phoneme discriminationinthefirstyearoflife are associated with varying levels of vocabulary development years later. Recent progress, primarily in the developing visual system, has begun to unravel the biological basis of this critical period timing.
Crucially, the onset and time-course of these windows of opportunity and vulnerability are governed by the actions of GABAergic interneurons. Manipulation of parvalbumin-positive (PV+) interneurons in particular, through genetic or pharmacological disruption, can prematurely trigger or delay critical period opening — effectively dissociating critical periods from chronological age. Conversely, novel molecular regulators of neuromodulatory systems or perineuronal nets in the extracellular matrix surrounding PV+ cells actively dampen plasticity beyond the critical period to maintain circuit stability. Lifting these “brakes” in adulthood can reopen juvenile levels of brain plasticity.
In other words, critical period timing is itself plastic. These results carry striking implications for humans. Genetic or environmental risk factors, such as drug exposures, will effectively shift the normal trajectory of brain development. For example, gestational exposure to serotonin reuptake inhibitors is associated with premature closure of a critical period for phoneme discrimination. In mouse models of autism spectrum disorders, altered PV+ circuit maturation leads to accelerated or delayed critical period timing, which may, in part, underlie the emergent cognitive dysfunction. In turn, circuitbased strategies can now be leveraged for treating brain injury or correcting aberrant development in adulthood.