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8.20神経生化学セミナーのご案内その2/Neurochemistry Seminar Announcement

Title: "Multiple levels of NMDA receptor-dependent synapse regulation"
Lecturer: Bernardo Sabatini&s_comma; M.D.&s_comma; Ph.D.
Affiliation: Department of Neurobiology&s_comma; Harvard Medical School&s_comma; Boston&s_comma;
Massachusetts&s_comma; USA

Time: August 20&s_comma; 2007 (Mon) 14:00~15:00
Place: Room 202 (Seminar Room 2)&s_comma; 2nd floor&s_comma; New Medical Research Building
Host: Haruhiko Bito&s_comma; Department of Neurochemistry (03-5841-3560)
Supported by Neuroscience Lecture Series&s_comma; Center for Integrated Brain Medical
Science&s_comma; a 21st Century COE Program from MEXT.

NMDA-type glutamate receptors (NMDARs) regulate many aspects of
neurotransmission in the mammalian brain. Here we present our work in
hippocampal pyramidal neurons examining the pathways that lie upstream of NMDARs
to regulate synaptically-evoked potentials and calcium transients as well as
those that lie downstream of NMDARs to regulate the number of synapses. We show
that the activation of NMDARs in spines of these cells is regulated by a complex
feedback loop that signals through voltage-sensitive sodium and calcium channels
to dampen NMDAR opening. In particular&s_comma; synaptically-evoked depolarization
within active spines opens R-type voltage-sensitive calcium channels that permit
calcium to enter which&s_comma; in turn&s_comma; activates SK-type calcium activated potassium
channels (SK). SK channels rapidly repolarize the spine membrane&s_comma; dampening the
synaptic potential and NMDAR-mediated calcium influx. In addition&s_comma; we show that
the growth and maintenance of excitatory synapses does not require opening of
NMDARs but does require the physical presence of the receptor. Furthermore&s_comma; the
obligatory NR1 subunit of the NMDAR signals through its C-terminal domain to
maintain normal numbers of synapses and spines. Lastly&s_comma; we show how
perturbations of NMDAR signaling by the amyloid-beta protein may contribute to
the pathogenesis of neurological symptoms in Alzheimer’s disease. In
collaboration with the laboratory of Dr. Dennis Selkoe&s_comma; we have found that
oligomers of amyloid-beta reduce NMDAR-mediate calcium influx in active spines
and&s_comma; over time&s_comma; triggers the loss of excitatory synapses. The amyloid-beta
mediated synapse loss requires signaling through calcineurin and cofilin&s_comma;
suggested that amyloid-beta oligomers promote the activation of pathways
involved in long-term depression and spine shrinkage. In summary&s_comma; our results
highlight the many levels at which NMDARs can be regulated and the multiple
roles these receptors play in controlling synaptic transmission in normal and
disease states.

脳神経医学専攻 神経生化学分野
〒113-0033 東京都文京区本郷7-3-1
e-mail: hbito@m.u-tokyo.ac.jp
Tel: 03-5841-3559 Fax: 03-3814-8154