[Abstract Title]. - Society for Neuroscience

Poster
238. LTD: Hippocampus and Cortex
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 238.10/D55
Topic: B.08.f. Long-term depression ( LTD )
Support: NIH Grant NIA5R01AG027443-02
Title: Soluble amyloid ß-protein facilitates NMDAR-dependent long-term synaptic depression
(LTD) by a novel mechanism
Authors: *S. LI 1 , S. HONG 2 , N. SHEPARDSON 2 , L. FEIG 3 , G. SHANKAR 2 , D. SELKOE 2 ;
1 Neurol., Brigham and Women's Hosp., Boston, MA; 2 Brigham and Women's Hosp., Boston,
MA; 3 Tufts Univ. Sch. of Med., Boston, MA
Abstract: Alzheimer‟s disease (AD) is characterized by insidious and progressive memory loss
accompanied by high levels of soluble amyloid-β proteins (Aβ) and the accumulation of amyloid
plaques and neurofibrillary tangles. Perhaps the strongest histopathological correlate of the
degree of dementia in AD subjects is the decrease in levels of cortical synapses, and APP
transgenic mice have decreased dendritic spine densities. Long-term potentiation (LTP) is
associated with spine formation or increase in spine volume, whereas the induction of long-term
depression (LTD) results in spine shrinkage and elimination. We and others have reported that
hippocampal LTP is inhibited by soluble oligomers of Aβ. Far less is known about the effect of
Aβ on LTD induction. Cell-secreted human Aβ from a hAPP-transfected CHO cell line (7PA2
cell medium) was used to study the effects of soluble Aβ on synaptic plasticity. Field excitatory
postsynaptic potentials (fEPSP) were recorded in stratum radiatum of CA1 in mouse
hippocampal slices, with the stimulating electrode in the Schaffer collaterals. LTD was induced
by 300 or 900 pulses at 1 Hz. We found that the LTD induced by 900 pulses in slices exposed to
cell-secreted Aß was resistant to the usual dose of NMDAR antagonist (50 κM AP5) that
prevents LTD in the absence of soluble Aß, but this “Aβ-mediated LTD” was prevented when
AP5 was combined with MK801. The Aβ-mediated LTD required extracellular Ca 2+ influx and
active PP2B and GSK-3 signaling pathways, in contrast to conventional NMDAR-mediated LTD
that requires low-level NMDAR activation and involves both extracellular and intracellular Ca 2+
sources and an active p38 MAPK signaling pathway. Using Ras-GRF1 knockout mice, in which
NMDA-mediated LTD (900 pusles protocol) cannot be induced in CA1, we confirmed this
distinct and novel Aβ-mediated LTD mechanism. Aβ-mediated LTD was mimicked by the
glutamate uptake inhibitor, TBOA, suggesting that soluble Aβ facilitates an LTD state in part
through reduced glutamate clearance.
Disclosures: S. Li , None; S. Hong, None; N. Shepardson, None; L. Feig, None; G. Shankar,
None; D. Selkoe, None.