A large variety of distinct GABAergic interneurons are present in the hippocampus. By releasing GABA into principal cells and interneurons, they exert a powerful control on neuronal excitability and are responsible for network oscillations crucial for information processing. Among these, the oriens-lacunosum moleculare (O-LM) interneurons have been intensively studied. These cells exhibit a prominent sag in electrotonic potentials induced by hyperpolarizing current pulses of increasing intensity, mediated by the time-dependent inwardly rectifying cationic current I_h.

Here, whole cell patch clamp recordings in current and voltage clamp mode were used to study whether nicotine, the active component of tobacco, is able to modulate I_h and the oscillatory activity of O-LM interneurons in the CA1 region of the hippocampus. To target these neurons we used hippocampal slices from transgenic mice expressing EGFP in a subset of somatostatin containing interneurons. In a first set of experiments, the sub threshold resonance behavior of these cells was characterized by measuring voltage responses to sinusoidal currents of constant amplitude and linearly increasing frequency (ZAP stimulus), before and during bath application of a low concentration (1 mM) of nicotine, close to that present in the smoker's blood immediately after smoking a cigarette. In the presence of nicotine, at -90 mV (but not at -70 mV), a frequency-selective enhancement of the voltage response in the range of 2-3 Hz was found. This was associated with a mean impedance increase of 439 % (439 ± 143 %; P=0.02; n=6). This effect was mimicked by ZD7288 (100 mM), indicating that it was due to a reduction in amplitude of I_h. Nicotine applied to neurons voltage clamped at -50 mV, strongly reduced I_h in a voltage-dependent way (nicotine-induced conductance change, measured at the end of the voltage step, was 89 + 10 % at -70 mV and 49 + 13 % at -90 mV; n=7; P=0.01 at -90 mV). Dose-response experiments revealed an IC₅₀ of 60 nM. Bath application of DHbE (50 mM) or mecamyllamine (100 mM) failed to prevent nicotine effects on I_h suggesting that the action of nicotine was independent on nAChR activation. The blocking effect of nicotine on I_h was mimicked by the nicotine analogue epibatidine (300 nM) but not by acetylcholine (100 mM).

In conclusions, it is likely that, in O-LM interneurons, nicotine reduces I_h current by directly interfering with the HCN channel pore. This may influence the hippocampal oscillatory activity and rhythmogenesis in smokers.