Abstract
Acetylcholine (ACh) regulates network operation in the hippocampus by controlling excitation and inhibition in rat CA1 pyramidal neurons (PCs), the latter through gamma-aminobutyric acid type-A receptors (GABAARs). Although, the enhancing effects of ACh on GABAARs have been reported (Dominguez et al., 2014, 2015), its role in regulating tonic GABAA inhibition has not been explored in depth. Therefore, we aimed at determining the effects of the activation of ACh receptors on responses mediated by synaptic and extrasynaptic GABAARs. Here, we show that under blockade of ionotropic glutamate receptors ACh, acting through muscarinic type 1 receptors, paired with post-synaptic depolarization induced a long-term enhancement of tonic GABAA currents (tGABAA) and puff-evoked GABAA currents (pGABAA). ACh combined with depolarization also potentiated IPSCs (i.e., phasic inhibition) in the same PCs, without signs of interactions of synaptic responses with pGABAA and tGABAA, suggesting the contribution of two different GABAA receptor pools. The long-term enhancement of GABAA currents and IPSCs reduced the excitability of PCs, possibly regulating plasticity and learning in behaving animals.
Highlights
Acetylcholine (ACh) plays a fundamental role in the regulation of network operation in the hippocampus (Watanabe et al, 2006; Connelly et al, 2013; Dominguez et al, 2014, 2015)
We analyzed the long-term effects of acetylcholine application paired with post-synaptic depolarization on both tonic and phasic GABAA inhibition in CA1 PCs
Tonic inhibition results through activation by low concentrations of ambient GABA of slow desensitizing high-affinity voltagesensitive extrasynaptic gammaaminobutyric acid type-A receptors (GABAARs) (Kullmann, 2000; Semyanov et al, 2004; Glykys and Mody, 2007; Pavlov et al, 2009; Brickley and Mody, 2012)
Summary
Acetylcholine (ACh) plays a fundamental role in the regulation of network operation in the hippocampus (Watanabe et al, 2006; Connelly et al, 2013; Dominguez et al, 2014, 2015). In PCs ACh can induce a long-term potentiation (LTP) of excitatory synapses through post-synaptic mechanisms (Markram and Segal, 1990; Fernandez de Sevilla et al, 2008; Fernandez de Sevilla and Buno, 2010; Dennis et al, 2015). ACh can control inhibitory synapses in PCs both through presynaptic (Wu and Saggau, 1997; Alger, 2002; Kano et al, 2009) and post-synaptic mechanisms (Kittler and Moss, 2003; Bannai et al, 2009; Castillo et al, 2011; Luscher et al, 2011; Dominguez et al, 2014, 2015). GABAARs elicit the tonic current (tGABAA), which hyperpolarizes CA1 PCs, reduces network excitability (Semyanov et al, 2003; Semyanov et al, 2004), and regulates information processing
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