title: Adenosine A1 Receptor Suppresses Tonic GABAA Receptor Currents in Hippocampal Pyramidal Cells and in a Defined Subpopulation of Interneurons.
abstract: Adenosine is an endogenous neuromodulator that decreases excitability of hippocampal circuits activating membrane-bound metabotropic A1 receptor (A1R). The presynaptic inhibitory action of adenosine A1R in glutamatergic synapses is well documented, but its influence on inhibitory GABAergic transmission is poorly known. We report that GABAA receptor (GABAAR)-mediated tonic, but not phasic, transmission is suppressed by A1R in hippocampal neurons. Adenosine A1R activation strongly inhibits GABAAR agonist (muscimol)-evoked currents in Cornu Ammonis 1 (CA1) pyramidal neurons and in a specific subpopulation of interneurons expressing axonal cannabinoid receptor type 1. In addition, A1R suppresses tonic GABAAR currents measured in the presence of elevated ambient GABA as well as in naïve slices. The inhibition of GABAergic currents involves both protein kinase A (PKA) and protein kinase C (PKC) signaling pathways and decreases GABAAR δ-subunit expression. On the contrary, no A1R-mediated modulation was detected in phasic inhibitory postsynaptic currents evoked either by afferent electrical stimulation or by spontaneous quantal release. The results show that A1R modulates extrasynaptic rather than synaptic GABAAR-mediated signaling, and that this modulation selectively occurs in hippocampal pyramidal neurons and in a specific subpopulation of inhibitory interneurons. We conclude that modulation of tonic GABAAR signaling by adenosine A1R in specific neuron types may regulate neuronal gain and excitability in the hippocampus.
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal Unidade de Neurociências, Instituto de Medicina Molecular, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Diogo M
authors.initials: DM
authors.lastname: Rombo
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal Unidade de Neurociências, Instituto de Medicina Molecular, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Raquel B
authors.initials: RB
authors.lastname: Dias
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal Unidade de Neurociências, Instituto de Medicina Molecular, Universidade de Lisboa, Lisboa, Portugal Neuropaediatrics Department, Hospital D. Estefânia, Centro Hospitalar Lisboa Central, Lisboa, Portugal.
authors.forename: Sofia T
authors.initials: ST
authors.lastname: Duarte
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal Unidade de Neurociências, Instituto de Medicina Molecular, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Joaquim A
authors.initials: JA
authors.lastname: Ribeiro
authors.affiliation: Medical Research Council Anatomical Neuropharmacology Unit, Department of Pharmacology, Oxford University, Oxford, UK.
authors.forename: Karri P
authors.initials: KP
authors.lastname: Lamsa
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal Unidade de Neurociências, Instituto de Medicina Molecular, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Sebastião
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007395:Interneurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008297:Male; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000378:metabolism; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D043682:Receptor, Adenosine A1; D011963:Receptors, GABA-A; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C
keywords: GABAergic interneurons; disinhibition; network excitability; neuromodulation; tonic and phasic inhibition