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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.
- Source :
-
Journal of neuroscience research [J Neurosci Res] 2016 Jun; Vol. 94 (6), pp. 568-78. Date of Electronic Publication: 2015 Aug 26. - Publication Year :
- 2016
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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.<br /> (© 2015 Wiley Periodicals, Inc.)
- Subjects :
- 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
Amygdala drug effects
Fragile X Mental Retardation Protein metabolism
Fragile X Syndrome pathology
GABA Modulators pharmacology
Membrane Potentials drug effects
gamma-Aminobutyric Acid metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4547
- Volume :
- 94
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of neuroscience research
- Publication Type :
- Academic Journal
- Accession number :
- 26308557
- Full Text :
- https://doi.org/10.1002/jnr.23632