Abstract
Critical periods are discrete developmental stages when the nervous system is especially sensitive to stimuli that facilitate circuit maturation. The distinctive landscapes assumed by the developing CNS create analogous periods of susceptibility to pathogenic insults and responsiveness to therapy. Here, we review critical periods in nervous system development and disease, with an emphasis on the neurodevelopmental disorder DYT1 dystonia. We highlight clinical and laboratory observations supporting the existence of a critical period during which the DYT1 mutation is uniquely harmful, and the implications for future therapeutic development.
Authors
Jay Li, Sumin Kim, Samuel S. Pappas, William T. Dauer
Figure 1
A neurodevelopmental model of DYT1 pathogenesis.
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Timeline of molecular, cellular, and behavioral events in Dlx-CKO mice, as well as concurrent and potentially related developmental processes (109 , 140 ). Molecular and cellular phenotypes emerge throughout a discrete period of vulnerability to torsinA impairment during early postnatal CNS maturation. These phenotypes rapidly disappear or stabilize, but motor dysfunction persists for life. This model highlights that initial torsinA-linked molecular events can lead to permanent circuit dysfunction delinked from the initial genetic insult. The sources for the phenotypes defined are as follows: NE blebbing (84 ), perinuclear ubiquitin accumulation, cholinergic interneuron (ChI) degeneration, and motor dysfunction (94 ). Illustrated by Rachel Davidowitz.
