Nicotine‐induced switch in the nicotinic cholinergic mechanisms of facilitation of long‐term potentiation induction

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Abstract
Nicotine facilitates the induction of long‐term potentiation (LTP) in the hippocampal CA1 region. The present study reveals the potential mechanisms underlying this effect of nicotine. Timed ACh‐mediated activation of α7 nicotinic acetylcholine receptors (nAChRs) on pyramidal cells is known to promote LTP induction. Nicotine could suppress this timing‐dependent mechanism by desensitizing nAChRs. Timed ACh‐mediated activation of α7 nAChRs on feedforward interneurons can prevent LTP induction by inhibiting pyramidal cells. Nicotine diminished this ACh‐mediated inhibition by desensitizing α7 nAChRs, thereby reducing the inhibitory influence on pyramidal cells. In addition to these desensitizing effects, nicotine activated presynaptic non‐α7 nAChRs on feedforward interneurons to decrease the evoked release of γ‐aminobutyric acid (GABA) onto pyramidal cells. Furthermore, nicotine increased the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) in pyramidal cells, and concomitantly caused a reduction in the size of responses to focal GABA application onto the dendrites of pyramidal cells, suggesting that the nicotine‐induced increase in interneuronal activity leads ultimately to a use‐dependent depression of evoked IPSCs in pyramidal cells. These nicotine‐induced suppressions of inhibition of pyramidal cells were accompanied by enhanced N‐methyl‐d‐aspartate (NMDA) responses in pyramidal cells. Thus, our results suggest that nicotine promotes the induction of LTP by diminishing inhibitory influences on NMDA responses while suppressing the ACh‐mediated mechanisms. These ACh‐independent mechanisms probably contribute to the nicotine‐induced cognitive enhancement observed in the presence of cholinergic deficits, such as those in Alzheimer's disease patients.