Postsynaptic activity reverses the sign of the acetylcholine-induced long-term plasticity of GABA(A) inhibition

作者:Dominguez Soledad; Fernandez de Sevilla David; Buno Washington*
来源:Proceedings of the National Academy of Sciences of the United States of America, 2014, 111(26): E2741-E2750.
DOI:10.1073/pnas.1321777111

摘要

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 GABA(A) inhibition (GABA(A)-LTP). Indeed, this enhanced inhibition is due to the increased activation of alpha(5)beta gamma(2) subunit-containing GABA(A) receptors by the GABA released. GABA(A)-LTP requires the activation of M1-muscarinic receptors and an increase in cytosolic Ca2+. 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.

  • 出版日期2014-7-1