Why does life experience exert a greater influence on the developing brain? In childhood, brain development is punctuated by a series of ‘critical periods’ during which specific brain circuits are most sensitive to experience. These critical periods help refine wiring within the brain that is essential for normal function. Thereafter, the diminished capacity for flexibility, or ‘plasticity’, in the adult brain impedes recovery from childhood neurologic disorders. Thus, understanding how plasticity is regulated has significant therapeutic potential.

My research group investigates how disruption or mistiming of critical periods adversely affects brain development as well as how to ‘re-open’ critical periods later in life to improve therapeutic outcomes. We explore the genes and mechanisms that mediate the transition from robust plasticity during critical periods in the developing brain to more restricted plasticity in the mature brain with a combination of conditional mouse genetics, electrophysiology, imaging of neuronal activity and structure in vivo, and head-fixed/freely-moving behavioural assays. Our goal is to devise interventions that acutely enhance brain plasticity to promote more efficient and complete restitution of function from childhood neurologic disorders including amblyopia (lazy eye), Fragile X Syndrome, and autism spectrum disorders.

Current Projects

1. Identify the genes and signaling pathways that contribute to closing the critical period for visual plasticity.
Much of our current work focuses on understanding how the nogo-66 receptor gene (ngr1) functions to close the critical period for ocular dominance (OD) in the developing visual system. Mice lacking a functional ngr1 gene retain OD plasticity into adulthood and recovery normal vision in a murine model of amblyopia (McGee, 2005; Stephany, 2014). Improved understanding of this neuronal signaling pathway may yield new approaches to ‘re-activate’ developmental plasticity.

2. Characterize critical-period and adult visual plasticity at cellular and circuit resolution.
We are employing genetically-encoded calcium sensors in combination with head-fixed behaviours to observe the progression of visual plasticity in wild-type mice and different mutant mouse strains that possess enhanced (e.g. ngr1) or impaired (e.g. fmr1) visual plasticity across time, cell type, and cortical layer. These studies will advance understanding of visual plasticity from a static and all-or-nothing phenomenon to a series of cell-type specific and laminar specific time-dependent changes to the circuitry of visual cortex.

3. Determine how genes implicated in autism spectrum disorders disrupt brain circuitry mediating perceptual learning.
We have discovered a correlation between developmental visual plasticity and tactile learning. Adult mice lacking ngr1 retain critical-period visual plasticity and perform better on a whisker-dependent learning task than wild-type mice, whereas mice lacking a functional gene for fragile x mental retardation 1 (fmr1), a murine model for Fragile X Syndrome, display both impaired OD plasticity and tactile learning. In studies combining head-fixed behaviours, electrophysiology, and imaging of neuronal activity in vivo, we are investigating how task performance and improvement differentially alters cortical circuitry in these mouse strains. 

Key Publications

Stephany CÉ, Ikrar T, Nguyen C, Xu X, McGee AW. Nogo receptor 1 confines a disinhibitory microcircuit to the critical period in visual cortex. J Neurosci. 2016 Oct 26 36(43):11006-12 

Frantz MG, Kast RJ, Dorton HM, Chapman KS, McGee AW. Nogo receptor 1 limits ocular dominance plasticity but not turnover of axonal boutons in a model of amblyopia. Cereb Cortex. 2016 May;26(5):1975-85

 Stephany CÉ, Chan LL, Parivash SN, Dorton HM, Piechowicz M, Qiu S, McGee AW. Plasticity of binocularity and visual acuity are differentially limited by nogo receptor. J Neurosci. 2014 Aug 27;34(35):11631-40 

Arnett MT, Herman DH, McGee AW. Deficits in tactile learning in a mouse model of fragile X syndrome. PLoS One. 2014 Oct 8;9(10)

Park JI, Frantz MG, Kast RJ, Chapman KS, Dorton HM, Stephany CÉ, Arnett MT, Herman DH, McGee AW.Nogo receptor 1 limits tactile task performance independent of basal anatomical plasticity. PLoS One. 2014 Nov 11;9(11)