Smoking during pregnancy is an important public health problem associated with a wide range of adverse developmental effects. The offspring of smokers have an elevated risk of tobacco smoking, cognitive deficits, and impaired learning and memory during adolescence, but little is known about the mechanisms underlying these effects. Animal studies support the view that nicotine, the principle neuroactive component of tobacco, is responsible for these effects. The effects of nicotine are mediated by its interaction with nicotinic acetylcholine receptors (nAChRs). Thus, inappropriate stimulation of nAChRs is most likely responsible for the development of adverse effects during adolescence. During early postnatal development, ?-aminobutyric acid (GABA)ergic interneurons play a critical role in neural circuit formation. Our central hypothesis is that maternal nicotine exposure causes inappropriate GABA release in the hippocampus, a brain region associated with memory formation, via nAChRs, resulting in a long-lasting disturbance of circuit operation extending into adolescence. Hippocampal CA1 pyramidal cells, which provide the major output of the hippocampus, receive two major excitatory synaptic inputs either directly or indirectly from the neocortex. Nicotine modulates synaptic transmission and long-term potentiation (LTP;one form of synaptic plasticity considered to be a cellular substrate of learning and memory) induction in opposite directions at these pathways via activation of the ?2 nAChR subtype. This subtype, the most sparsely expressed nAChR subtype in the brain, shows a distinct localization in a subset of GABAergic interneurons in the hippocampus and its activation also modulates LTP induction in these interneurons. These observations suggest that this subtype is an important component in hippocampal circuitry involved in cognitive function. Because this nAChR subtype is continuously activated in the presence of nicotine, maternal nicotine-induced adverse effects may be due to altered functioning of ?2* nAChR-expressing interneurons. The goal of this project is to determine whether maternal nicotine exposure influences the functioning of ?2* nAChR-expressing interneurons, affecting normal circuit operation and, therefore, information processing in the hippocampus. To achieve this goal, we will deliver a chronic nicotine dose during early postnatal development, and subsequently examine synaptic functioning in hippocampal slices prepared from the rats at various developmental stages, using electrophysiological and optical recording techniques, as well as morphological and molecular biological techniques.
The specific aims are to determine whether maternal nicotine exposure affects: 1) the expression of ?2* nAChRs and the number of ?2* nAChR- expressing interneurons, 2) the operation of circuits, 3) the operation of inhibitory circuits, 4) the nicotinic modulation of N-methyl-D-aspartate receptor responses in pyramidal cells, and 5) the induction of LTP in ?2* nAChR-expressing interneurons and at the two major excitatory synapses. Results from these studies will help determine not only the cellular basis of maternal smoking-induced cognitive impairments, but may also aid in the development of an effective prevention against maternal smoking-induced cognitive impairments by targeting the ?2 nAChR subtype.

Public Health Relevance

Maternal smoking during pregnancy elevates the risk of attentional and cognitive deficits during adolescence. The proposed experiments will test the hypothesis that maternal nicotine exposure causes inappropriate stimulation of nicotinic acetylcholine receptors in the hippocampus, a brain region associated with memory formation, which results in a long-lasting disturbance of neural circuit operation, and therefore affecting the mechanisms underlying learning and memory during adolescence. Results from the proposed experiments will help determine the cellular basis of maternal smoking-induced cognitive deficits in children.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Wu, Da-Yu
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University of California Irvine
Other Basic Sciences
Schools of Arts and Sciences
United States
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