Deficient tonic GABAergic conductance and synaptic balance in the fragile X syndrome amygdala.
Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability. Comorbidities of FXS such as autism are increasingly linked to imbalances in excitation and inhibition (E/I) as well as dysfunction in GABAergic transmission in a number of brain regions including the amygdala. However, the link between E/I imbalance and GABAergic transmission deficits in the FXS amygdala is poorly understood. Here we reveal that normal tonic GABAA receptor-mediated neurotransmission in principal neurons (PNs) of the basolateral amygdala (BLA) is comprised of both δ- and α5-subunit-containing GABAA receptors. Furthermore, tonic GABAergic capacity is reduced in these neurons in the Fmr1 knockout (KO) mouse model of FXS (1.5-fold total, 3-fold δ-subunit, and 2-fold α5-subunit mediated) as indicated by application of gabazine (50 μM), 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 1 μM), and α5ia (1.5 μM) in whole cell patch-clamp recordings. Moreover, α5-containing tonic GABAA receptors appear to preferentially modulate nonsomatic compartments of BLA PNs. Examination of evoked feedforward synaptic transmission in these cells surprisingly revealed no differences in overall synaptic conductance or E/I balance between wild-type (WT) and Fmr1 KO mice. Instead, we observed altered feedforward kinetics in Fmr1 KO PNs that supports a subtle yet significant decrease in E/I balance at the peak of excitatory conductance. Blockade of α5-subunit-containing GABAA receptors replicated this condition in WT PNs. Therefore, our data suggest that tonic GABAA receptor-mediated neurotransmission can modulate synaptic E/I balance and timing established by feedforward inhibition and thus may represent a therapeutic target to enhance amygdala function in FXS.
Center for Neuroscience Research, Children's National Medical Center, Washington, District of Columbia; Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, District of Columbia; and.
Brandon S
BS
Martin
Center for Neuroscience Research, Children's National Medical Center, Washington, District of Columbia;
Joshua G
JG
Corbin
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences and Department of Pediatrics, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado molly.huntsman@ucdenver.edu.
Molly M
MM
Huntsman
D000679:Amygdala / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D019706:Excitatory Postsynaptic Potentials; D025461:Feedback, Physiological; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000378:metabolism*; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology; D053444:Inhibitory Postsynaptic Potentials; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D010793:Phthalazines / Q000494:pharmacology; D021122:Protein Subunits / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology
D051860:Fragile X Messenger Ribonucleoprotein 1; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007555:Isoxazoles; D010793:Phthalazines; D021122:Protein Subunits; D011724:Pyridazines; D011963:Receptors, GABA-A; D014230:Triazoles; C555638:3-(5-methylisoxazol-3-yl)-6-((1-methyl-1,2,3-triazol-4-yl)methyloxy)-1,2,4-triazolo(3,4-a)phthalazine; C497684:Fmr1 protein, mouse; C049853:gabazine; C015542:gaboxadol
GABA; amygdala; fragile X syndrome; tonic inhibition