Cellular and Molecular Neurobiology; nicotinic cholinergic control of synaptic plasticity; learning and memory and addiction
The nicotinic cholinergic system is one of the major modulatory neurotransmitter systems in the brain and has been implicated in learning, memory formation, and drug addiction. My laboratory provides an integrated environment that combines molecular biological and electrophysiological facilities for the study of molecular and cellular mechanisms underlying nicotinic cholinergic function. My research focuses on nicotinic cholinergic control of synaptic plasticity in the hippocampus with the goal of identifying new targets for the development of new medications and therapies for cognitive impairment and nicotine abuse.
Nicotine and long-term potentiation (LTP): Long-term potentiation of glutamatergic synaptic transmission in the hippocampus is widely regarded to be the cellular substrate of learning and memory, and its induction critically depends on the activation of N-methyl-D-aspartate receptors (NMDARs). Nicotine promotes the induction of LTP via activation and inactivation (via desensitization) of different nicotinic acetylcholine receptors. One of our projects is to elucidate the mechanism underlying nicotine-induced enhancement of NMDAR responses, which results in facilitation of LTP induction. Dual whole-cell recordings in the hippocampal slice, combined with molecular biological and morphological approaches are being used.
Genes affected by long-term nicotine use: Both continued use of drugs of abuse and the process of memory storage resulting in learning cause long-lasting neural changes in the brain that appear to involve modifications of glutamatergic synaptic transmission. A recent finding from our lab is that in vivo chronic nicotine administration promotes the induction of LTP in rats. This change is accompanied by altered gene expression, indicating that gene expression has a crucial role in mediating the response to long-term nicotine use. We are using cDNA arrays to profile gene expression changes in the hippocampus after chronic nicotine exposure and nicotine withdrawal, as a first step toward the identification of genes underlying the effect of long-term nicotine use.
Virus-mediated gene transfer in the hippocampus: We are interested in developing virus-mediated gene transfer systems to overexpress or knockout specific gene function for the study of nicotinic cholinergic function. Nicotine has been shown to improve learning and memory in Alzheimer patients and protect hippocampal neurons against the toxicity caused by b-amyloid, a peptide implicated in the formation of plaques in Alzheimer disease brains. Study of the mechanisms underlying these nicotine effects will be greatly accelerated by the development of an animal model of Alzheimer's disease. We are assessing a non-transgenic animal model for Alzheimer's disease produced by virus-mediated gene transfer of the amyloidogenic fragment of amyloid precursor protein.
Kammesheidt, A., Ito, K.-I., Kato, K., Villarreal, L. and Sumikawa, K. (1996) Transduction of hippocampal CA1 by adenovirus in vivo. Brain Res. 736: 297-304.
Kammesheidt, A., Kato, K., Ito, K.-I., and Sumikawa, K. (1997) Adenovirus-mediated NMDA receptor knockouts in the rat hippocampal CA1 region. NeuroReport 8: 635-638.
Fujii, S., Ji, Z., Morita, N., and Sumikawa, K. (1999) Acute and chronic nicotine exposure differentially facilitate the induction of LTP. Brain Res. 846: 137-143.
Fujii, S., Jia, Y., Yang, A., and Sumikawa, K. (2000) Nicotine reverses GABAergic inhibition of long-term potentiation induction in the hippocampal CA1 region. Brain Res. 863: 259-265.
Fujii, S. and Sumikawa, K. (2001) Nicotine accelerates reversal of long-term potentiation and enhances long-term depression in the rat hippocampal CA1 region. Brain Res. 894: 340-346.
Fujii, S. and Sumikawa, K. (2001) Acute and chronic nicotine exposure reverse age-related declines in the induction of LTP in the hippocampus of aged rats. Brain Res. 894: 347-353.
Yamazaki, Y., Hamaue, N. and Sumikawa, K. (2002) Nicotine compensates for the loss of cholinergic function to enhance long-term potentiation induction, Brain Res. 946: 148-152.
Yamazaki, Y., Jia, Y., Hamaue, N., and Sumikawa, K. (2005) Nicotine-induced switch in the nicotinic cholinergic mechanisms of facilitation of long-term potentiation induction. Eur. J. Neurosci. 22: 845-860.
Yamazaki, Y., Jia, Y., Niu, R., and Sumikawa, K. (2006) Nicotine exposure in vivo induces long-lasting enhancement of NMDA receptor-mediated currents in the hippocampus. Eur. J. Neurosci. 23: 1819-1828.
Guan, X., Nakauchi, S., and Sumikawa, K. (2006) Nicotine reverses consolidated long-term potentiation in the hippocampal CA1 Region. Brain Res. 1078: 80-91.
Yamazaki, Y., Fujii, S., Jia, Y., and Sumikawa, K. (2006) Nicotine withdrawal suppresses nicotinic modulation of long-term potentiation induction in the hippocampal CA1 region. Eur. J. Neurosci. 24: 2903-2916.
Nakauchi, S., Yamazaki, Y., and Sumikawa, K. (2006) Chronic nicotine exposure affects the normal operation of hippocampal circuits. NeuroReport (in press).
Yamazaki, Y., Jia, Y., Wong, J. K., and Sumikawa, K. (2006) Chronic nicotine-induced switch in Src-family kinase signaling for long-term potentiation induction in hippocampal CA1 pyramidal cells. Eur. J. Neurosci. 24: 3271-3284.
Society for Neuroscience
American Society for Cell Biology
Neurobiology and Behavior