title: Postsynaptic activity reverses the sign of the acetylcholine-induced long-term plasticity of GABAA inhibition.
abstract: Acetylcholine (ACh) regulates forms of plasticity that control cognitive functions but the underlying mechanisms remain largely unknown. ACh controls the intrinsic excitability, as well as the synaptic excitation and inhibition of CA1 hippocampal pyramidal cells (PCs), cells known to participate in circuits involved in cognition and spatial navigation. However, how ACh regulates inhibition in function of postsynaptic activity has not been well studied. Here we show that in rat PCs, a brief pulse of ACh or a brief stimulation of cholinergic septal fibers combined with repeated depolarization induces strong long-term enhancement of GABAA inhibition (GABAA-LTP). Indeed, this enhanced inhibition is due to the increased activation of α5βγ2 subunit-containing GABAA receptors by the GABA released. GABAA-LTP requires the activation of M1-muscarinic receptors and an increase in cytosolic Ca(2+). In the absence of PC depolarization ACh triggered a presynaptic depolarization-induced suppression of inhibition (DSI), revealing that postsynaptic activity gates the effects of ACh from presynaptic DSI to postsynaptic LTP. These results provide key insights into mechanisms potentially linked with cognitive functions, spatial navigation, and the homeostatic control of abnormal hyperexcitable states.
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain; and.
authors.forename: Soledad
authors.initials: S
authors.lastname: Domínguez
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain; andDepartamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Fernández de Sevilla
authors.affiliation: Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain; and wbuno@cajal.csic.es.
authors.forename: Washington
authors.initials: W
authors.lastname: Buño
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D004558:Electric Stimulation; D009473:Neuronal Plasticity / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1 / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D055366:Synaptic Potentials / Q000502:physiology*
chemical_list: D043643:Receptor, Muscarinic M1; D011963:Receptors, GABA-A; D000109:Acetylcholine; D002118:Calcium
keywords: LTP of inhibition; endocannabinoids; intracellular Ca2+; outward rectification