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J Neurosci Res ; 94(6): 568-78, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26308557

ABSTRACT

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 γ-aminobutyric acidergic (GABAergic) transmission provided by peri- and extrasynaptic GABA type A (GABAA ) 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 GABAA 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 GABAA receptors as its parent molecule, allopregnanolone. Furthermore, at submicromolar concentrations (≤1 µM), SGE-872 is selective for tonic, extrasynaptic α4ß3δ-containing GABAA receptors over typical synaptic α1ß2γ2 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 GABAA receptors containing α4 subunits may represent a novel and highly useful therapeutic avenue for ASDs and related disorders involving hyperexcitability of neuronal networks.


Subject(s)
Amygdala/drug effects , Fragile X Mental Retardation Protein/metabolism , Fragile X Syndrome/pathology , GABA Modulators/pharmacology , Membrane Potentials/drug effects , gamma-Aminobutyric Acid/metabolism , Amygdala/metabolism , Amygdala/pathology , Animals , Animals, Newborn , CHO Cells , Cricetulus , Disease Models, Animal , Dose-Response Relationship, Drug , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/genetics , GABA Agents/pharmacology , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , In Vitro Techniques , Membrane Potentials/genetics , Mice , Mice, Knockout , Patch-Clamp Techniques , Pregnanolone/analogs & derivatives , Pregnanolone/chemistry , Pregnanolone/pharmacology , Receptors, GABA-A/genetics , Receptors, GABA-A/metabolism , Transfection , gamma-Aminobutyric Acid/pharmacology
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