Nicotinic and GABAergic Interactions in Hippocampal Development

University Of California, San Diego, La Jolla CA

Investigators

Abstract

[unreadable] DESCRIPTION (provided by applicant): One of the most abundant nicotinic acetylcholine receptors (nAChRs) in brain is a species containing a7 subunits. These a7-nAChRs have a high relative calcium permeability, which enables them to regulate diverse events in neurons. Highest a7-nAChR levels are found in the hippocampus during early postnatal life. Our recent work shows that these receptors cluster on dendritic filopodia and tend to colocalize with GABA(A) receptors. The filopodia receive convergent input from cholinergic and GABAergic axons, and the cholinergic innervation requires a7-nAChR activation for stabilization. Other studies from our group indicate that GABAergic and nicotinic signaling interact during development to promote synapse formation. Mice lacking functional aV-nAChRs retain GABAergic signaling in an excitatory mode, characteristic of the immature state, for a longer period during postnatal life than do their wild type counterparts. Both the excitatory phase and the initial inhibitory phase of GABAergic signaling, acting together with excitatory nicotinic input can direct neuronal development and synapse formation. How this interaction occurs and the ultimate consequences in vivo are not known. This proposal will test hypotheses about the developmental consequences of endogenous signaling through a7-nAChRs. Further, it will test possible mechanisms mediating the nicotinic effect on GABAergic signaling. The hypotheses derive directly from our recent results on nicotinic/GABAergic interactions and the role of BDNF in regulating nicotinic receptors on specific subpopulations of hippocampal interneurons. The experiments will employ imaging, genetic manipulation and electrophysiological analysis both in slice culture and on fresh slices from wild type and nAChR- knockout mutant mice. Two Specific Aims are identified: (1) Use a7-nAChR knockout mice to examine receptor effects on hippocampal innervation. (2) Examine the role of BDNF and nicotinic signaling in the control of development. These experiments are likely to provide fundamental information about the role of nicotinic signaling in shaping the developing hippocampus. Health Relevance: The research proposed will increase our understanding of how nicotinic signaling affects synapse formation and GABAergic development in the hippocampus. These processes are likely to be important not only for fetal and postnatal development but also are likely to be relevant for plasticity/learning and addiction in the adult. Understanding how nicotine affects these processes will give greater insight into mechanisms supporting human development and those contributing to and influenced by drug addiction. [unreadable] [unreadable] [unreadable]