Smoking during pregnancy is an important public health problem associated with a wide range of adverse neonatal and developmental effects. The offspring of smokers display attentional and cognitive deficits and impaired learning and memory, but little is known about the potential mechanisms of 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 synaptic and behavioral deficits later in life. During early postnatal development, GABAergic 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 sustained activation of a specific nAChR subtype on interneurons, resulting in a long-lasting disturbance of circuit operation. Hippocampal CA1 pyramidal cells, which provide the major output of the hippocampus, receive two major excitatory synaptic inputs directly or indirectly from the neocortex. Nicotine modulates synaptic transmission and long-term potentiation (LTP;one form of synaptic plasticity and considered to be a cellular substrate of learning and memory) induction in opposite directions at these pathways via the activation of the a2 nAChR subtype. The expression of this subtype in GABAergic interneurons is upregulated during early postnatal development. The goals of the proposed project are to explore whether the sustained activation of the a2 nAChR subtype on GABAergic interneurons in fetal brains affects the functional development of hippocampal circuits. To achieve these goals, we will deliver a chronic nicotine dose during early development, and subsequently examine synaptic function in hippocampal slices prepared from adolescent wild-type and a2 knockout mice using electrophysiological and optical recording techniques.
The specific aims are to determine whether maternal nicotine exposure affects: 1) synaptic transmission and LTP induction at the two pathways in an a2 nAChR-dependent manner, and 2) nicotinic modulation of synaptic transmission and LTP induction at the two pathways in an a2 nAChR-dependent manner. 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 a2 nAChRs. The offspring of smokers display attentional and cognitive deficits and impaired learning and memory, but little is known about the potential mechanisms of these effects. During early postnatal development, GABAergic interneurons play a critical role in neural circuit formation. The proposed experiments will test the hypothesis that maternal nicotine exposure causes inappropriate GABA release in the hippocampus, a brain region associated with memory formation, via sustained activation of a specific nicotinic acetylcholine receptor (nAChR) subtype on interneurons, resulting in a long-lasting disturbance of circuit operation. This project will help determine not only the cellular basis of maternal smoking-induced cognitive impairments, but also may aid in the development of an effective prevention against maternal smoking-induced cognitive impairments by targeting a specific nAChR subtype.
