title: 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.
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 α4β3δ-containing GABAA receptors over typical synaptic α1β2γ2 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.
authors: Center for Neuroscience Research, Children's National Medical Center, Washington, DC.
authors: Brandon S
authors: BS
authors: Martin
authors: SAGE Therapeutics, 215 First Street, Cambridge, MA 0214243.
authors: Gabriel
authors: G
authors: Martinez-Botella
authors: SAGE Therapeutics, 215 First Street, Cambridge, MA 0214243.
authors: Carlos M
authors: CM
authors: Loya
authors: SAGE Therapeutics, 215 First Street, Cambridge, MA 0214243.
authors: Francesco G
authors: FG
authors: Salituro
authors: SAGE Therapeutics, 215 First Street, Cambridge, MA 0214243.
authors: Albert J
authors: AJ
authors: Robichaud
authors: Pharmaceutical Sciences and Department of Pediatrics, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
authors: Molly M
authors: MM
authors: Huntsman
authors: SAGE Therapeutics, 215 First Street, Cambridge, MA 0214243.
authors: Mike A
authors: MA
authors: Ackley
authors: SAGE Therapeutics, 215 First Street, Cambridge, MA 0214243.
authors: James J
authors: JJ
authors: Doherty
authors: Center for Neuroscience Research, Children's National Medical Center, Washington, DC.
authors: Joshua G
authors: JG
authors: Corbin
mesh_terms: D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D016466:CHO Cells; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology*; D018682:GABA Agents / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D011280:Pregnanolone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D018682:GABA Agents; D018757:GABA Modulators; D006574:Heterocyclic Compounds, 2-Ring; D011280:Pregnanolone; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C497684:Fmr1 protein, mouse; C000613451:SGE-872
keywords: GABA; GABAA receptor; amygdala; fragile X syndrome; positive allosteric modulator