Low birth weight, hyperactivity and reduced cognitive ability have been conslstely reported in children whose mothers smoked during pregnancy. Similar effects have been observed in animals chronically exposed to nicotine during gestation. Prenatal nicotine significantly affects hippocampal development in rat pups, which may underlie the observed deficits in cognitive functions. Nicotine acts via nicotinic acetylcholine receptors (nAChR), which are pentameric ion channels composed of alpha and beta subunits. Nicotinic receptors are widely expressed in adult and developing brain, and their activation by nicotine triggers a variety of cellular responses, including calcium influx into neurons and activation of intracellular signaling cascades. Chronic activation of nAChRs can be neuroprotective in response to neurotoxins, exitotoxicity, or beta amyloid toxicity, leading to increased survival of neurons. In addition, chronic nicotine exposure has been shown to increase the expression of growth factors in the adult hippocampus which could lead to increased neurotrophic tone and, together with the neuroroptective effects of nAChR activation, lead to increased neuronal survival. These properties could be beneficial in an aging brain, but could have detrimental consequences in the developing brain by interfering with developmentally regulated cell death. During hippocampal development, pioneer GABAergic neurons are numerous during late prenatal and early postnatal ages. A part of this transient population undergoes preprogrammed developmental cell death, whereas others differentiate into mature GABAergic intemeurons during the second postnatal week. Our studies indicate that nicotinic receptors are strongly expressed in the developing hippocampus and can be activated by nicotine. Therefore, chronic nicotine treatment during a critical period of postnatal development when preprogrammed cell death takes place could alter the survival of pioneer neurons and interfere with the maturation of the GABAergic system in the hippocampus. GABA is the principal inhibitory neurotransmitter in the adult hippocampus and an increase in the number of GABAergic neurons could interfere with hippocampal transmission and impair cognitive functions in the adult. We will test the hypothesis that chronic nicotine exposure during early postnatal timepoints leads to changes in the developing hippocampus, including increased nAChR expression and increased expression of growth factors such as NGF, BDNF, or NT-3, resulting in increased numbers of GABAergic interneurons in the adult.
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