Sanna E1,2, Licheri V1, Talani G2
1Dept of Life & Environmental Sciences, University of Cagliari, Cagliari, Italy
2Institute of Neuroscience, National Research Council, Cagliari, Italy
It is widely accepted that ligand-gated and voltage-dependent ion channels are crucial in mediating many of the central pharmacological and behavioral actions of ethanol (EtOH). Recent studies reported that the function of hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels expressed in VTA neurons as well as hippocampal interneurons are modulated by EtOH, suggesting that they may represent an additional sensitive target for this drug. HCN channels are encoded by four HCN genes (HCN1-4), and their activation generates a typical inward current, termed Ih, which plays an important role in controlling neuronal resting membrane potential and firing rate of action potentials, and are heavily implicated in dendritic integration of post-synaptic potentials. Since HCN are highly expressed in CA3 glutamatergic pyramidal neurons, we have investigated the action of EtOH on Ih in these hippocampal cells from Sprague-Dawley juvenile rats, and attempted to characterize the possible involvement of the AC/cAMP/PKA intracellular pathway. Our results show that EtOH modulates HCN-mediated Ih in a biphasic manner, with lower concentrations (20 mM) of EtOH enhancing Ih amplitude, and higher concentrations (60-80 mM) producing an inhibitory effect. This biphasic action of EtOH is reflected by parallel changes in carbachol-induced firing rate and dendritic synaptic integration of AMPA receptor-mediated EPSPs. The modulatory effect of EtOH on Ih could be completely antagonized by the selective inhibitors of adenylyl cyclase (AC) and PKA, DDA and H89, respectively. Moreover, forskolin, an activator of AC, mimicked the biphasic action of EtOH by increasing, at 0.1 M, the amplitude of Ih, and, at 30 M, producing an opposite effect. Altogether, the results demonstrate that EtOH modulates the function of HCN channels expressed in CA3 pyramidal neurons, with a mechanism possibly involving the AC/cAMP/PKA intracellular pathway. Overall, these finding suggest that the biphasic modulatory action of EtOH on HCN channels may contribute to the effects of this drug on the excitability of the hippocampal formation.
Funded by grant from Regione Autonoma della Sardegna, Prog CRP3_63 LR7/2007-bando 2010.