UC Irvine

Approximately 10 percent of the children born in the United States each year are exposed to cigarette smoke in utero, putting them at heightened risk for many physical and cognitive problems. Here we used mouse and rat models of early developmental nicotine exposure in order to elucidate the hippocampal changes that underlie nicotine-induced memory impairment. We observed that mice exposed to nicotine during their first two postnatal weeks showed significantly impaired long-term hippocampus-dependent spatial memory, but normal short-term spatial memory and long-term hippocampus-independent recognition memory. We also observed several changes in CA1 hippocampal function in these nicotine-treated mice, including facilitated LTP, heightened network activity, and dysfunctional nicotinic modulation of network activity and LTP. Thus, we next used an α2 knockout mouse line to explore the hypothesis that early life nicotine exposure, by downregulating α2-containing nicotinic acetylcholine receptors (nAChRs), causes this spatial memory deficit and these changes in hippocampal function. We found that α2 knockout mice showed a similar pattern of memory impairments as did those treated with early postnatal nicotine. Additionally, our findings suggest that abnormal activation of α2-containing nAChRs by early life nicotine is necessary to bring about the facilitation of LTP and heightened CA1 network activity we observed in nicotine-exposed mice. Because α2-containing nAChRs are only found in the hippocampus on oriens-lacunosum moleculare (OLM) interneurons, which modulate inputs to the CA1 region of the hippocampus from the CA3 and entorhinal cortex, these findings add to the recently emerging body of evidence that OLM cells play a critical role in learning and memory. Furthermore, our work suggests that α2-containing nAChRs are important mediators of the effect of developmental nicotine on the hippocampus, and may therefore be a valuable target for the development of therapeutics to treat the cognitive impairments induced by in utero nicotine exposure.