UC San Diego

Nicotinic acetylcholine receptors (nAChRs) are a class of ligand-gated ion channels that are found throughout the central nervous system where they participate in higher order cognitive functions as well as neurological disorders. The nAChRs reach peak levels during early postnatal life. The hippocampus, a forebrain structure essential for memory, expresses high concentrations of nAChRs, which are important in the maturation of GABAergic signaling. This dissertation explores the role of nAChRs in shaping the functional organization and maturation of the developing hippocampus. In early development nAChRs containing the [alpha]7 subunit ([alpha]7-nAChRs) are found postsynaptically on interneurons. Brain-derived neurotrophic factor acts through glutamatergic signaling to upregulate [alpha]7-nAChRs levels on a subset of interneurons, namely those that innervate pyramidal neurons. Levels of [alpha]7-nAChRs are unaffected on interneurons that inhibit other interneurons and pyramidal cells. To study the role of activity in nicotinic synapse development, septal explants were placed alongside hippocampal slices in organotypic cultures. The septal explants send out cholinergic and GABAergic processes which invaded the hippocampal slice to form functional synapses, allowing the study of nicotinic signaling in synapse formation in culture. The [alpha]7-nAChR and GABAA[alpha]1 receptors are found colocalized at the tips of filopodia where they receive convergent cholinergic and GABAergic innervation. When [alpha]7-nAChRs are blocked, filopodia become more motile and cholinergic synapses are lost, suggesting that the formation or stabilization of nicotinic synapses is activity-dependent. Nicotine rapidly induces spines in hippocampal slice culture by acting through [beta]2-containing ([beta]2*) nAChRs on the presumptive postsynaptic cell. Activation of [alpha]7- nAChRs is necessary to recruit presynaptic contacts and postsynaptic glutamatergic receptors to dendrites. Similar processes exist in vivo. Direct infusion of nicotine into the hippocampus induces spines, while young animals lacking both [alpha]7- and [beta]2*-nAChRs show a reduced number of spines. Susceptibility to nicotine is restricted to early development; nicotine is unable to induce spines in older animals. Together these results show that nAChRs have diverse functions in the developing nervous system, helping to form both cholinergic and noncholinergic synapses. The location and regulation of nAChRs receptors are, therefore, likely to have a long-lasting impact on hippocampal connectivity