title: ASIC1a activation enhances inhibition in the basolateral amygdala and reduces anxiety.
abstract: The discovery that even small changes in extracellular acidity can alter the excitability of neuronal networks via activation of acid-sensing ion channels (ASICs) could have therapeutic application in a host of neurological and psychiatric illnesses. Recent evidence suggests that activation of ASIC1a, a subtype of ASICs that is widely distributed in the brain, is necessary for the expression of fear and anxiety. Antagonists of ASIC1a, therefore, have been proposed as a potential treatment for anxiety. The basolateral amygdala (BLA) is central to fear generation, and anxiety disorders are characterized by BLA hyperexcitability. To better understand the role of ASIC1a in anxiety, we attempted to provide a direct assessment of whether ASIC1a activation increases BLA excitability. In rat BLA slices, activation of ASIC1a by low pH or ammonium elicited inward currents in both interneurons and principal neurons, and increased spontaneous IPSCs recorded from principal cells significantly more than spontaneous EPSCs. Epileptiform activity induced by high potassium and low magnesium was suppressed by ammonium. Antagonism of ASIC1a decreased spontaneous IPSCs more than EPSCs, and increased the excitability of the BLA network, as reflected by the pronounced increase of evoked field potentials, suggesting that ASIC1a channels are active in the basal state. In vivo activation or blockade of ASIC1a in the BLA suppressed or increased, respectively, anxiety-like behavior. Thus, in the rat BLA, ASIC1a has an inhibitory and anxiolytic function. The discovery of positive ASIC1a modulators may hold promise for the treatment of anxiety disorders.
authors.affiliation: Department of Anatomy, Physiology, and Genetics, Department of Psychiatry, and Program in Neuroscience, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814.
authors.forename: Volodymyr I
authors.initials: VI
authors.lastname: Pidoplichko
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Aroniadou-Anderjaska
authors.forename: Eric M
authors.initials: EM
authors.lastname: Prager
authors.forename: Taiza H
authors.initials: TH
authors.lastname: Figueiredo
authors.forename: Camila P
authors.initials: CP
authors.lastname: Almeida-Suhett
authors.forename: Steven L
authors.initials: SL
authors.lastname: Miller
authors.forename: Maria F M
authors.initials: MF
authors.lastname: Braga
mesh_terms: D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D064751:Ammonium Compounds / Q000494:pharmacology; D000679:Amygdala / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D003623:Dark Adaptation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005480:Flurbiprofen / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000145:classification / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D062565:Acid Sensing Ion Channels; D064751:Ammonium Compounds; D000894:Anti-Inflammatory Agents, Non-Steroidal; C568268:Asic1 protein, rat; D018691:Excitatory Amino Acid Antagonists; D058787:GABA-A Receptor Antagonists; D005680:gamma-Aminobutyric Acid; D005480:Flurbiprofen
keywords: ASIC1a; GABAergic inhibition; acid-sensing ion channels; anxiety; basolateral amygdala; epileptiform activity