Modulation of Hyperpolarization-Activated Cation Currents (Ih) by Ethanol in Rat Hippocampal CA3 Pyramidal Neurons

It is well established that ethanol (EtOH), through the interaction with several membrane proteins, as well as intracellular pathways, is capable to modulate many neuronal function. Recent reports show that EtOH increases the firing rate of hippocampal GABAergic interneurons through the positive modulation of the hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels. This effect might be consistent with the increase of GABA release from presynaptic terminals observed in both CA1 and CA3 inhibitory synapses that leads the enhancement of the GABAergic system induced by EtOH. The activation of HCN produced an inward currents that are commonly called Ih. Ih play an important role for generating specific neuronal activities in different brain regions, including specific sub-regions of the hippocampal formation, such as CA1 and CA3 pyramidal neurons and hippocampal GABAergic interneurons. The main physiologic effect mediated by HCN-induced Ih is directed to the control of the neuronal resting membrane potential and action potential (AP) discharge as well as dampen synaptic integration. Since robust Ih are also present in CA3 glutamatergic neurons, I here investigated whether the action of EtOH in the control of CA3 excitability can be correlated with its possible direct interaction with these cation channels. For this purpose, patch-clamp experiments were performed in CA3 pyramidal neurons from hippocampal coronal slices obtained from male Sprague-Dawley rats. The data obtained demonstrated that EtOH is able to modulate Ih in biphasic manner depending on the concentrations used. Low EtOH concentrations enhanced Ih amplitude, while high reversibly reduced them. This biphasic action induced by EtOH reflects on firing rate and synaptic integration. In addition, in this reports it has been shown that EtOH modulates the function of HCN channels through interfering with the cAMP/AC/PKA intracellular pathways, an effect that is mimicked also by other endogenous compounds such as dopamine through D1 receptors activation. These data suggest that the HCN-mediated Ih currents in CA3 pyramidal neurons are sensitive to EtOH action, which at low or relevant concentrations is able to increase or reduce their function respectively. Altogether these data suggest a potential new mechanism of EtOH actions on hippocampal formation and may help to better understand the depressant central activity showed by this drug of abuse