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

• Published in: Journal of neuroscience research 2016-06, Vol.94 (6), p.568-578
• Main Authors: Martin, Brandon S., Martinez-Botella, Gabriel, Loya, Carlos M., Salituro, Francesco G., Robichaud, Albert J., Huntsman, Molly M., Ackley, Mike A., Doherty, James J., Corbin, Joshua G.
• Format: Article
• Language: English
• Subjects: amygdala; Amygdala - drug effects; 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 Mental Retardation Protein - metabolism; fragile X syndrome; Fragile X Syndrome - genetics; Fragile X Syndrome - pathology; GABA; GABA Agents - pharmacology; GABA Modulators - pharmacology; GABAA receptor; gamma-Aminobutyric Acid - metabolism; gamma-Aminobutyric Acid - pharmacology; Heterocyclic Compounds, 2-Ring - chemistry; Heterocyclic Compounds, 2-Ring - pharmacology; In Vitro Techniques; Membrane Potentials - drug effects; Membrane Potentials - genetics; Mice; Mice, Knockout; Patch-Clamp Techniques; positive allosteric modulator; Pregnanolone - analogs & derivatives; Pregnanolone - chemistry; Pregnanolone - pharmacology; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; Transfection
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.23632

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. © 2015 Wiley Periodicals, Inc. This study shows the efficacy of a novel, selective positive allosteric modulator of tonic GABAA receptors (SGE‐872) for rescuing GABAergic deficits associated with amygdala dysfunction in fragile X syndrome. The findings highlight SGE‐872 as a new tool to modulate tonic (α4‐containing) over phasic (α1‐containing) GABAA receptors.