Rescue of deficient amygdala tonic γ‐aminobutyric acidergic currents in the Fmr–/y mouse model of fragile X syndrome by a novel γ‐aminobutyric acid type A receptor‐positive allosteric modulator

Alterations in the ratio of excitatory to inhibitory transmission are emerging as a common component of many nervous system disorders, including autism spectrum disorders (ASDs). Tonic -aminobutyric acidergic (GABAergic) transmission provided by peri- and extrasynaptic GABA type A (GABA(A)) receptors powerfully controls neuronal excitability and plasticity and, therefore, provides a rational therapeutic target for normalizing hyperexcitable networks across a variety of disorders, including ASDs. Our previous studies revealed tonic GABAergic deficits in principal excitatory neurons in the basolateral amygdala (BLA) in the Fmr1(-/y) knockout (KO) mouse model fragile X syndrome. To correct amygdala deficits in tonic GABAergic neurotransmission in Fmr1(-/y) KO mice, we developed a novel positive allosteric modulator of GABA(A) receptors, SGE-872, based on endogenously active neurosteroids. This study shows that SGE-872 is nearly as potent and twice as efficacious for positively modulating GABA(A) receptors as its parent molecule, allopregnanolone. Furthermore, at submicromolar concentrations (1 M), SGE-872 is selective for tonic, extrasynaptic 43-containing GABA(A) receptors over typical synaptic 122 receptors. We further find that SGE-872 strikingly rescues the tonic GABAergic transmission deficit in principal excitatory neurons in the Fmr1(-/y) KO BLA, a structure heavily implicated in the neuropathology of ASDs. Therefore, the potent and selective action of SGE-872 on tonic GABA(A) receptors containing 4 subunits may represent a novel and highly useful therapeutic avenue for ASDs and related disorders involving hyperexcitability of neuronal networks. (c) 2015 Wiley Periodicals, Inc.