Cortical interneuron hypofunction in Fragile X Syndrome

The Department of Neurobiology and Behavior will host Carlos Portera Cailliau, from the Department of Neurology & Neurobiology of the University of California, Los Angeles, for a James L. McGaugh Distinguished Lecture.

Abstract

Cortical circuit dysfunction is a primary pathophysiology in neurodevelopmental disorders (NDDs). Considering how symptoms in NDDs/autism become apparent in toddlers, circuit changes must emerge very early in cortical development.  Over the last decade, developmental differences in cortical synaptic dynamics, neuronal adaptation, and network synchrony have been reported in the Fmr1 knockout (KO) mouse model of Fragile X Syndrome (FXS), a prototypical NDD.  In addition, the density, maturity and activity of parvalbumin (PV) cortical interneurons are all reduced in Fmr1 KO mice and in other autism mouse models.  We find that the density of PV neurons in S1 is reduced in both juvenile and adult Fmr1 KO mice, as well as in post-mortem tissue from human FXS cases.  Furthermore, the density and the firing of Nkx2.1-expressing interneuron precursors are also reduced in early Fmr1 KO mice. Increasing MGE-derived interneuron activity using excitatory DREADDs significantly increases the density of PV cells at P15. Moreover, increasing PV cell firing in Fmr1 KO mice with a novel allosteric modulator of Kv3.1 channels improves deficits in the tuning and the adaptation of excitatory neurons in S1 to repetitive whisker stimulation.