Functional mapping of GABA A receptor subtypes in the amygdala.
The physiological significance of the large diversity of GABA A receptors is poorly understood. Using mice, which carry a point mutation that renders specific subtypes of GABA A receptors diazepam insensitive, it was recently discovered that particular types of GABA A receptors are involved in specific, behaviorally relevant signaling pathways. We have used these mice to study inhibitory synaptic transmission in the amygdala. GABA A receptor-mediated inhibitory postsynaptic currents (IPSCs) per se were not affected by the point mutations. Their modulation by diazepam, however, was altered depending on the genotype of the mice studied. Based on the different responses to diazepam, we found that IPSCs in the lateral/basolateral amygdala were mediated by both alpha2- and alpha1-subunit-containing GABA A receptors whereas those in the central amygdala were mediated only by alpha2-subunit-containing GABA A receptors. Immunohistochemical staining corroborated these findings at a morphological level. To investigate a possible link between interneuron and receptor diversity, we selectively depressed release from the subset of GABAergic terminals carrying type 1 cannabinoid receptors. These receptors are known to modulate amygdala-mediated behavior. Application of a type 1 cannabinoid receptor agonist resulted in a selective reduction of inhibitory current mediated by alpha1-subunit-containing GABA A receptors. Mice with specific diazepam-insensitive GABA A receptor subtypes therefore provide a novel tool to investigate GABA A receptor distribution and the organization of inhibitory circuits at a functional level. The crucial role of the amygdala for the mediation of anxiety is in agreement with the part that alpha2-subunit-containing GABA A receptors play in anxiolysis and their important function in this area of the brain.
Marowsky
Anne
A
Institute of Pharmacology and Toxicology, University of Zürich, Winterthurerstrasse 190, CH-8057, Switzerland.
Fritschy
Jean-Marc
JM
Vogt
Kaspar E
KE
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001640:Bicuculline / Q000378:metabolism / Q000494:pharmacology; D003975:Diazepam / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D017354:Point Mutation / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D021122:Protein Subunits; D011963:Receptors, GABA-A; D003975:Diazepam; D001640:Bicuculline