Glutamatergic pathways comprise the principal excitatory networks in the central nervous system, employing a combination of synapses on dendritic spines and shafts to position neurons in circuits. How synaptogenesis can be coordinated across neuronal populations during development to form these networks remains poorly understood. Our preliminary results suggest a profound and novel role for endogenous nicotinic signaling in this process;it appears to be a major force driving development of glutamatergic pathways and determining the kinds of connections formed. Nicotinic activity results from the transmitter acetylcholine (ACh) activating ionotropic nicotinic ACh receptors (nAChRs). The receptors appear early in postnatal life and initially mediate spontaneous waves of excitation in many brain regions. The two most abundant nAChR subtypes are ?7- containing homopentamers (?7-nAChRs) and ?2-containing heteropentamers (?2*-nAChRs). Our preliminary results with brain tissue from mice lacking ?7-nAChRs (constitutive knockouts) using multiple methods suggests that the receptors are required for neurons to receive proper numbers of functional glutamatergic synapses during early postnatal life. Preliminary results with mice lacking ?2*-nAChRs indicates the receptors provide a complementary role, increasing the number of dendritic spines available to receive glutamatergic synapses. In this proposal we combine genetic manipulation, imaging, patch-clamp recording, network labeling, and ultrastructural analysis to examine how nicotinic activity influences the synaptic composition of networks in vivo.
Three Specific Aims are proposed. The first tests the hypothesis that endogenous nicotinic cholinergic signaling determines the number, location, and possibly source of glutamatergic synapses on neurons in early postnatal brain and that the effects persist into the adult, determining the ratio of glutamatergic/GABAergic input a neuron receives. The second tests the hypothesis that early exposure to nicotine in vivo, at levels encountered by smokers, disrupts normal development, produces excessive glutamatergic contacts, and imposes long-lasting changes in neural circuits. The third tests the hypothesis that nicotinic control of spine formation is rapid and local, whereas nicotinic control of synapse formation involves microRNAs for broad coordination of gene expression. The experiments employ new methods, including mapping techniques in vivo to distinguish network changes and physiological methods to assess functional consequences. The findings are likely to have major import both for prevailing views about nicotinic cholinergic function during development and for understanding mechanisms guiding network construction. The results will have direct biomedical relevance in revealing mechanisms by which early nicotine exposure is likely to produce long-lasting behavioral impairments that continue in adults. Targets may be suggested for therapeutic intervention to protect against or compensate for prior nicotine exposure. These results will represent a major step forward in understanding nervous system development and identifying key vulnerabilities.

Public Health Relevance

This proposal will examine signaling pathways in the developing brain that are co-opted by nicotine and will determine whether they play critical roles in shaping the formation of excitatory networks. Results obtained here are likely to provide new insight into mechanisms controlling brain development and may identify long- lasting detrimental effects of early nicotine exposure that account for reported behavioral deficits. Biomedically, the results may also suggest targets for therapeutic intervention and remedial action, offering some good news to counter the bad.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS012601-36A1
Application #
8297694
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Stewart, Randall R
Project Start
1979-05-01
Project End
2016-12-31
Budget Start
2012-02-01
Budget End
2012-12-31
Support Year
36
Fiscal Year
2012
Total Cost
$338,515
Indirect Cost
$119,765
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
Gomez-Varela, David; Berg, Darwin K (2013) Lateral mobility of presynaptic *7-containing nicotinic receptors and its relevance for glutamate release. J Neurosci 33:17062-71
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
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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