Nicotine Blocks the Hyperpolarization-Activated Current Ih and Severely Impairs the Oscillatory Behavior of Oriens-Lacunosum Moleculare Interneurons

In the brain, high cognitive functions are encoded by coherent network oscillations. Key players are inhibitory interneurons that, by releasing GABA into principal cells, pace targeted cells. Among these, oriens-lacunosum moleculare (O-LM) interneurons that provide a theta frequency patterned output to distal dendrites of pyramidal cells are endowed with HCN channels responsible for the slowly activating inwardly rectifying I-h current and their pacemaking activity. Here we show that, intransgenic mice expressing EGFP(enhanced green fluorescent protein) in a subset of stratum oriens somatostatin-containing interneurons that mostly comprise O-LM cells, nicotine, the active component of tobacco, reduced I-h and the oscillatory behavior of O-LM interneurons. In cells hyperpolarized at -90 mV, nicotine suppressed the theta resonance in the same way as ZD 7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride), a selective blocker of I-h. Nicotine blocked I-h in a concentration-dependent way with an EC50 of 62 nM. Similar effects were produced by epibatidine, a structural analog of nicotine. The effects of nicotine and epibatidine were independent on nicotinic ACh receptor (nAChR) activation because they persisted in the presence of nAChR antagonists. Furthermore, nicotine slowed down the interspike depolarizing slope and the firing rate, thus severely disrupting the oscillatory behavior of O-LM cells. Molecular modeling suggests that, similarly to ZD 7288, nicotine and epibatidine directly bind to the inner pore of the HCN channels. It is therefore likely that nicotine severely influences rhythmogenesis and high cognitive functions in smokers.