Cigarette smoking during pregnancy can have severe impacts on the mental and physical health of offspring, including long-lasting impairments in IQ and memory. Still, as of 2010 an estimated 12.3% of expectant mothers in the United States continued smoking. Cigarette smoke has been shown to contain more than 8,000 chemicals, but among these nicotine is thought to be the leading neuroteratogen. Several studies using rodent models of perinatal nicotine treatment have demonstrated that exposure to nicotine during early development causes long-lasting deficits in learning and memory. However, the outstanding question in the field remains which cellular and molecular changes induced by nicotine underlie this cognitive impairment. The first two weeks of postnatal development of rodents, which is roughly equivalent to the third trimester of human development, is a critical time for neurogenesis and synaptogenesis in the hippocampus, a brain region associated with memory formation. In order to identify long-lasting cellular, molecular and circuitry changes in the hippocampus that may underlie nicotine-induced cognitive impairments, we use a model of early postnatal nicotine exposure in rodents that targeted this critical period of hippocampal development. We have tested our model to show that it results in impaired memory, and used electrophysiological, pharmacological and voltage sensitive dye imaging techniques to identify nicotine-induced changes in hippocampal function. We found several changes in hippocampal network activity, synaptic plasticity and nicotinic modulation of hippocampal function, all associated with the ?2 nicotinic acetylcholine receptor (nAChR) subtype, that could be the cause of memory deficits. The ?2* nAChR, the most sparsely expressed nAChR subtype in the brain, has long been ignored in the study of nicotine's central action. However, we have shown that this subtype, which is selectively expressed in GABAergic interneurons in the stratum oriens/alveus, is an important component in the hippocampal circuitry gating information flow and long-term potentiation (LTP; considered to be a cellular substrate of learning and memory). Furthermore, our results suggest the importance of ?2* nAChRs in hippocampus- dependent memory, and lay the foundation for further studies of the mechanisms underlying cognitive impairment after maternal smoking. In the research proposed here, we will test the hypotheis that developmental nicotine exposure, by inappropriately activating ?2* nAChRs, causes functional alterations of ?2* nAChRs-expressing interneurons, and that these changes could be tied to maternal-nicotine-induced hippocampal memory impairments. Our major goals are to determine whether the ?2* nAChR indeed plays a causal role in maternal-nicotine-induced memory impairments, and whether the adverse effects can be rescued by pharmacological and optogenetic manipulations of ?2* nAChR-expressing interneurons. Given the very limited expression of ?2* nAChRs in the hippocampus, determinating their role in nicotine-induced cognitive deficits could yield a unique and powerful therapeutic target for children whose mothers smoked in pregnancy.
The children of mothers who smoked during pregnancy have an elevated risk of cognitive deficits, but little is known about the underlying mechanisms. The proposed experiments test the hypothesis that inappropriate stimulation of nicotinic acetylcholine receptors by early-life nicotine exposure results in the long-lasting disturbance of neuronal function in the hippocampus. Because the hippocampus is a brain region associated with memory formation, these changes would likely impair mechanisms of learning and memory. With a better understanding of nicotine-induced changes in the hippocampus, we can progress toward the development of therapies to prevent and treat smoking-related cognitive deficits in children.
