Deficits in ca1 hippocampal long-term potentiation in tg2576 mice and its potential reversal by pharmacological treatments
M.R. Bowlby, Q. Ji, T.A. Comery, R.L. Arias.
Society for Neuroscience, 855.4. (2004)
Discovery Neurosci., Wyeth Res., Princeton, NJ, USA
Long-term potentiation (LTP) is a common in vitro model of synaptic plasticity, learning and memory. A number of previous studies have demonstrated a deficit in LTP in some transgenic mouse models of Alzheimers disease, although various strains, ages and testing protocols have been used. In this study we examined theta-burst induced LTP in the CA1 region of the hippocampus in the tg2576 mouse model. The tg2576 strain expresses the Swedish double mutant form of the human amyloid-precursor protein. Excitatory post-synapic potentials (EPSPs) from acute hippocampal slices were recorded using glass field recording electrodes and multi-electrode arrays (MED-64 from Panasonic), in both submerged and interface configurations. Slices taken from tg2576 heterozygous animals 20-25 weeks of age, when compared with their wild-type littermate controls, showed impaired LTP at > 1hr post induction, while post-tetanic potentiation (PTP) was normal. EPSPs were also significantly smaller, with a lower slope than controls. Slices from younger mice (13-16 weeks old) showed no apparent deficit in LTP or PTP, although EPSPs showed a clear deficit in their input-output curves in comparison to wild-types. This deficit may be an early indicator of hippocampal dysfunction in these mice. Paired-pulse facilitation was not altered in these mice. Reversal of the deficits was examined by various treatments, including those modulating beta-amyloid production as well as agonists of several receptor systems. Treatment of mice 3 hrs prior to slice harvesting as well as incubating the tissue directly (with 100 M) with 100 mg/kg DAPT, a gamma-secretase inhibitor, did not reverse the deficits observed in the 20-25 week old mice. Agonists for several transmitter systems, however, may be able to rescue LTP in tg2576 mice, and/or enhance LTP in slices from normal rats, thus allowing hope of cognitive benefit in the future.
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