Nicotinic cholinergic signaling uses the transmitter acetylcholine to activate ligand-gated ion channels that are cation-selective in mammals. This form of signaling is widespread in the nervous system, reaches peak levels during early postnatal life, and continues throughout adulthood. It contributes to a variety of behaviors including arousal and cognition, participates in a number of neurodegenerative disorders including Alzheimer's and Parkinson's diseases, and is responsible for nicotine addiction. Despite intensive effort, little is understood about the role of nicotinic signaling during development when it drives spontaneous waves of excitation across the nervous system, and little is understood about the nicotinic mechanisms that subsequently exert global effects across networks in the adult brain. This proposal tests two novel hypotheses fundamental to these issues. The first is that nicotinic signaling during development promotes the formation of glutamatergic synapses both on early postnatal and adultborn neurons (Aims I &II). Since glutamatergic pathways provide the principal form of excitation in brain, this effect of nicotinic input is likely to have lasting consequences for nervous system function. The second hypothesis is that nicotinic activity in the adult brain can acutely and reversibly alter GABAergic signaling such that it stops being inhibitory and transiently becomes excitatory (Aim III). This could exert far-reaching effects across networks radically altering output. Preliminary studies performed on the hippocampus strongly support these ideas. The two major nicotinic acetylcholine receptors, homopentameric ?7-nAChRs and heteropentameric ?2-containing nAChRs, appear to complement each other in promoting glutamate synapse formation. One appears to act in cell-autonomous fashion to drive postsynaptic spine formation while the other may act indirectly to recruit components required for synaptic function. Preliminary results also support the second hypothesis: low levels of nicotine experienced by tobacco users may be sufficient to transiently invert the chloride gradient in adult neurons, thereby rendering GABA temporarily depolarizing. This could dramatically change the excitability of networks housing those neurons. The hypotheses will be tested by pharmacological and genetic manipulation, including loss-of-function and rescue experiments, performed on hippocampal slices and in vivo. The underlying molecular mechanisms will be analyzed and their consequences evaluated for system function. Imaging and electrophysiological approaches will be combined in this analysis. The experiments proposed here test pivotal ideas about the purpose of nicotinic cholinergic signaling in the nervous system. The results are likely to change how we think about fundamental processes guiding development and regulation of function in neural networks. The vulnerability of these processes to exploitation by tobacco-derived nicotine gives this work compelling health-related significance.

Public Health Relevance

This project will test new ideas about the roles of endogenous nicotinic cholinergic signaling in shaping the developing nervous system and controlling function subsequently in the adult. Because these are the same pathways hijacked by nicotine from tobacco consumption, the studies will also provide important information about the systems at risk and consequences likely to ensue. In addition to addressing fundamental aspects of nervous system function, the studies may identify targets for therapeutic intervention both to reverse or correct biological deficiencies and to mitigate the impact of habitual tobacco use.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035469-18
Application #
8448727
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Stewart, Randall R
Project Start
1996-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
18
Fiscal Year
2013
Total Cost
$319,617
Indirect Cost
$112,745
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Halff, Andrew W; Gómez-Varela, David; John, Danielle et al. (2014) A novel mechanism for nicotinic potentiation of glutamatergic synapses. J Neurosci 34:2051-64
Wang, Xulong; Lippi, Giordano; Carlson, David M et al. (2013) Activation of *7-containing nicotinic receptors on astrocytes triggers AMPA receptor recruitment to glutamatergic synapses. J Neurochem 127:632-43
Campbell, Nolan R; Fernandes, Catarina C; John, Danielle et al. (2011) Nicotinic control of adult-born neuron fate. Biochem Pharmacol 82:820-7
Berg, Darwin K (2011) Timing is everything, even for cholinergic control. Neuron 71:6-8
Fernandes, Catarina C; Berg, Darwin K; Gomez-Varela, David (2010) Lateral mobility of nicotinic acetylcholine receptors on neurons is determined by receptor composition, local domain, and cell type. J Neurosci 30:8841-51
Nai, Qiang; Wang, Xiaoyun; Jin, Ying et al. (2010) Ciliary neurotrophic factor enhances nicotinic synaptic transmission in sympathetic neurons. J Neurosci Res 88:887-95
Campbell, Nolan R; Fernandes, Catarina C; Halff, Andrew W et al. (2010) Endogenous signaling through alpha7-containing nicotinic receptors promotes maturation and integration of adult-born neurons in the hippocampus. J Neurosci 30:8734-44
Neff 3rd, Robert A; Conroy, William G; Schoellerman, Jeffrey D et al. (2009) Synchronous and asynchronous transmitter release at nicotinic synapses are differentially regulated by postsynaptic PSD-95 proteins. J Neurosci 29:15770-9
Neff 3rd, Robert A; Gomez-Varela, David; Fernandes, Catarina C et al. (2009) Postsynaptic scaffolds for nicotinic receptors on neurons. Acta Pharmacol Sin 30:694-701
Berg, Darwin K (2009) Silent synapses sit and wait for a better day. Neuron 61:157-9

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