Nicotinic Manipulation of the Hippocampus

Institution:	University of California, San Diego
Investigator(s):	Darwin Berg, Ph.D.
Award Cycle:	2007 (Cycle 16)	Grant #: 16RT-0167	Award: $420,000
Subject Area:	Nicotine Dependence
Award Type:	Research Project Awards

Abstracts

Initial Award Abstract

Repetitive relapse behavior is a hallmark feature of nicotine addiction, driving tobacco smoking and the health-related consequences it produces. After the initial withdrawal period, relapse is motivated largely by associative memories. Increasing evidence implicates the hippocampus, a specialized structure deep in the brain that is well-known to be required for many types of memory formation. We have recently shown that spontaneous activity in the brain, making use of the same pathways impacted by nicotine, normally drive maturation of brain cells and connections called synapses. This indicates a pervasive role for the pathways in shaping neural development and suggests a profound vulnerability to nicotine exposure, particularly in utero and early postnatal life. We have now obtained preliminary results indicating that signaling through these nicotine-sensitive mechanisms also has a more direct and equally profound effect on synapse formation in the developing hippocampus and that the mechanisms involved are likely to be important for synapse-dependent events such as learning in the adult as well. This proposal builds on these results to pursue two major areas of nicotinic action that are not well understood and yet are likely to have extensive impact on human health. The first is the issue of long-lasting changes induced by early exposure to nicotine, i.e. in utero and in early postnatal life from mother's milk and second-hand smoke. The changes are likely to involve synaptic changes that, if enacted during formative times, may have long-lasting effects on subsequent behavior. The second issue is the extent to which nicotine-induced long-term synaptic changes foster relapse behavior in the adult. Having identified naturally-occurring nicotinic mechanisms for shaping neural development, we will then determine how chronic nicotine exposure alters them. Moreover, we will initiate experiments to test pharmacological strategies for isolating and counteracting specific detrimental effects in vivo. Our specific aims to accomplish these goals are three-fold. 1) Examine the ability of one of the two major nicotinic receptor classes (the site of action of nicotine) in brain to drive synapse formation on hippocampal neurons. We will use postnatal tissue slices in culture to examine the composition, longevity, fate, and function of synapses formed. Hippocampal slices from normal and mutant mice lacking specific nicotinic receptors will be compared to assess the effects in vivo. 2) Test the ability of the other major nicotinic receptor class to enhance synaptic maturation. We will test the hypothesis that the other class of nicotinic receptors induces accumulation of specific components at the synapse to render them functional. We will compare levels of synapses in normal and mutant mice lacking each of the two nicotinic receptor classes and thereby will identify complementary and/or synergistic effects of the two receptor classes predicted from results in slice culture. 3) Determine the consequences of repeated nicotine exposure on synapse development in vivo and assess the protective effects of compounds that alter or block the ability of nicotine to affect nicotinic receptors. We will infuse/inject nicotine in the presence and absence of these test compounds in control and mutant mice during early postnatal and adult life to assess pharmacological strategies for protection against long-lasting nicotine-induced damage. Understanding how nicotine exposure affects synapse formation and function will provide insight into the cellular mechanisms by which drugs of abuse influence memory imprints and promote relapse. This information is likely to be valuable for devising pharmacological strategies for reversing or preventing nicotine-induced changes, thereby limiting the developmental impact and lessening relapse behavior.

Publications

Multiple cell adhesion molecules shaping a complex nicotinic synapse on neurons.
Periodical: Molecular and Cellular Neuroscience			Index Medicus:
Authors: Triana-Baltzer, GB; Lui, Z; Gounko, NV; and Berg, DK				ART
Yr: 2008	Vol:	Nbr: 39	Abs:	Pg: 74-82

Silent synapses sit and wait for a better day.
Periodical: Neuron			Index Medicus:
Authors: Berg, DK				ART
Yr: 2009	Vol:	Nbr: 61	Abs:	Pg: 157-159

Postsynaptic scaffolds for nicotinic receptors on neurons.
Periodical: Acta Pharmacol Sin			Index Medicus:
Authors: Nef, RA; Gomez-Varela, D; Fernandes, CC; and Berg, DK				ART
Yr: 2009	Vol:	Nbr:	Abs:	Pg:

Lateral diffusion of nicotini acetylcholine receptors on neurons depends on subunit composition and local domain.
Periodical: Society for Neuroscience Abstracts			Index Medicus:
Authors: Fernandes, CC; Berg, DK; and Gomez-Varela, D				ABS
Yr: 2009	Vol:	Nbr: 19	Abs: 10	Pg: 17-21

Nicotinic activity determines the number and location of glutamate synapses formed in the early postnatal hippocampus.
Periodical: Society for Neuroscience Abstracts			Index Medicus:
Authors: Halff, A; Gounko, NV; Duan, J-J; Berg, DK; and Lozada, AF.				ABS
Yr: 2009	Vol:	Nbr: 10	Abs: 09	Pg: 17-21

Multiple cell adhesion molecules shaping a complex nicotinic synapse on neurons.
Periodical: Molecular and Cellular Neuroscience			Index Medicus:
Authors: Triana-Baltzer, GB; Lui, Z; Gounko, NV; and Berg, DK				ART
Yr: 2008	Vol:	Nbr: 39	Abs:	Pg: 74-82

Silent synapses sit and wait for a better day.
Periodical: Neuron			Index Medicus:
Authors: Berg, DK				ART
Yr: 2009	Vol:	Nbr: 61	Abs:	Pg: 157-159

Postsynaptic scaffolds for nicotinic receptors on neurons.
Periodical: Acta Pharmacol Sin			Index Medicus:
Authors: Nef, RA; Gomez-Varela, D; Fernandes, CC; and Berg, DK				ART
Yr: 2009	Vol:	Nbr:	Abs:	Pg:

Lateral diffusion of nicotini acetylcholine receptors on neurons depends on subunit composition and local domain.
Periodical: Society for Neuroscience Abstracts			Index Medicus:
Authors: Fernandes, CC; Berg, DK; and Gomez-Varela, D				ABS
Yr: 2009	Vol:	Nbr: 19	Abs: 10	Pg: 17-21

Nicotinic activity determines the number and location of glutamate synapses formed in the early postnatal hippocampus.
Periodical: Society for Neuroscience Abstracts			Index Medicus:
Authors: Halff, A; Gounko, NV; Duan, J-J; Berg, DK; and Lozada, AF.				ABS
Yr: 2009	Vol:	Nbr: 10	Abs: 09	Pg: 17-21