Neuronal Circuit Dissection and Novel Therapeutic Strategies in Neurodevelopmental Disorders

Scientific Conference

Friday 17 April 2015 from 11:30 at 12:30

Speaker

Fagiolini Michela, PhD

• Assistant Professor, Neurology, Children’s Hospital, Harvard Medical School, Boston, MA

Dr Fagiolini’s research focuses on how neuronal cortical circuits are sculpted by sensory experience in early postnatal life. During her postdoctoral work in the Laboratory for Neuronal Circuit Development in Japan, Dr. Fagiolini has demonstrated that intracortical inhibition by a specific circuit connection directly control the timing, duration and closure of the classical critical period of ocular dominance plasticity. Since becoming an independent PI in 2007, she has focused her work on circuit dissection and treatment in neurodevelopmental disorders such as Rett Syndrome. She has discovered a clear visual cortical phenotype in mouse models of RTT and demonstrated its rescue by environmental and genetic manipulation (Durand et al, Neuron 2012). Interestingly, after an apparently normal onset of visual function, we find a progressive regression of visual acuity that directly correlates with the onset of RTT phenotype. Notably a selective inhibitory circuit, Parvalbumin-positive cells (PV), is hyper-connected very early in development resulting in silencing of cortical circuits. Strikingly, PV hyper-connectivity and visual acuity defects can be rescued by directly acting on mechanisms that normally control plasticity in developing cortical circuits: namely, sensory experience per se (dark rearing, DR) or NMDA receptor (NR2A) subunit composition. These results reveal a specific role for Mecp2 in the experience-dependent refinement of cortical circuits by regulating the excitation of pivotal inhibitory neurons. The identification of a particular receptor pathway within a specific cortical circuit offers an accessible membrane target for drug intervention strategies that do not rely on the re-expression of Mecp2 itself. These findings strongly suggest that visual processing in Rett syndrome patients may be altered and can be used as a robust biomarker of both cortical status and its response to therapy. To this end, in collaboration with the Rett Clinic at BCH, she has assessed the cortical function of the visual system in young girls with RTT and found significant morphological differences between groups, pointing to atypical development of early visual processing in patients and the need of further investigations.