Tonic GABAA-receptor-mediated inhibition in fragile-X syndrome: A cause of dysfunction or a pathway for a cure?

Abstract

Persistent conductance through tonically active extrasynaptic GABAA receptors provides dynamic and powerful regulation of neuronal networks. The adverse effects of reduced inhibitory function of this receptor system range from mood disorders and anxiety to epilepsy. Converging lines of evidence support the hypothesis that alterations in cellular excitability are a common mechanism underlying neurodevelopmental disorders including those in the autism spectrum. Fragile X syndrome (FXS) is a leading genetic cause of intellectual disability and a leading monogenetic cause of autism. Several aspects of the behavioral phenotype in both human and mouse models point to excitatory/inhibitory imbalances in key brain regions. While the prevailing theory implicates excessive glutamatergic signaling, recent evidence suggests that cellular and behavioral excitability may also derive from dysfunction in inhibitory neurotransmission. This chapter will highlight specific examples of defective and reduced GABAA-receptor-mediated tonic inhibitory neurotransmission as a contributing factor to the hyperexcitable phenotype observed in FXS.