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 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.
['Martin|Brandon S|BS|', 'Martinez-Botella|Gabriel|G|', 'Loya|Carlos M|CM|', 'Salituro|Francesco G|FG|', 'Robichaud|Albert J|AJ|', 'Huntsman|Molly M|MM|', 'Ackley|Mike A|MA|', 'Doherty|James J|JJ|', 'Corbin|Joshua G|JG|']
D000679:Amygdala D000818:Animals D000831:Animals, Newborn D016466:CHO Cells D003412:Cricetulus D004195:Disease Models, Animal D004305:Dose-Response Relationship, Drug D051860:Fragile X Mental Retardation Protein D005600:Fragile X Syndrome D018682:GABA Agents D018757:GABA Modulators D006574:Heterocyclic Compounds, 2-Ring D066298:In Vitro Techniques D008564:Membrane Potentials D051379:Mice D018345:Mice, Knockout D018408:Patch-Clamp Techniques D011280:Pregnanolone D011963:Receptors, GABA-A D014162:Transfection D005680:gamma-Aminobutyric Acid
amygdala fragile X syndrome GABA positive allosteric modulator GABAA receptor