Blockade of Long-Term Potentiation by b-Amyloid Peptides in the CA1 Region of the Rat Hippocampus In Vivo

Freir, Darragh B., Christian Holscher, and Caroline E. Herron. Blockade of long-term potentiation by b-amyloid peptides in the CA1 region of the rat hippocampus in vivo. J Neurophysiol 85: 708–713, 2001. The effect of intracerebroventricular (icv) injections of b-amyloid peptide fragments Ab[15–25], Ab[25–35], and Ab[35–25] were examined on synaptic transmission and long-term potentiation (LTP) in the hippocampal CA1 region in vivo. Rats were anesthetized using urethan, and changes in synaptic efficacy were determined from the slope of the excitatory postsynaptic potential (EPSP). Baseline synaptic responses were monitored for 30 min prior to icv injection of Ab peptides or vehicle. High-frequency stimulation (HFS) to induce LTP was applied to the Schaffer-collateral pathway 5 min or 1 h following the icv injection. HFS comprised 3 episodes of 10 stimuli at 200 Hz, 10 times, applied at 30-s intervals. Normal LTP measured 30 min following HFS, was produced following icv injection of vehicle (191 6 17%, mean 6 SE, n 5 6) or Ab[15–25; 100 nmol] (177 6 6%, n 5 6) 1 h prior to HFS. LTP was, however, markedly reduced by Ab[25–35; 10 nmol] (129 6 9%, n 5 6, P , 0.001) and blocked by Ab[25–35; 100 nmol] (99 6 6%, n 5 6, P , 0.001). Injection of the reverse peptide, Ab[35–25], also impaired LTP at concentrations of 10 nmol (136 6 3%, n 5 6, P , 0.01) and 100 nmol (144 6 7, n 5 8, P , 0.05). Using a different protocol, HFS was delivered 5 min following Ab injections, and LTP was measured 1 h post HFS. Stable LTP was produced in the control group (188 6 15%, n 5 7) and blocked by Ab[25–35, 100 nmol] (108 6 15%, n 5 6, P , 0.001). A lower dose of Ab[25–35; 10 nmol] did not significantly impair LTP (176 6 30%, n 5 4). The Ab-peptides tested were also shown to have no significant effect on paired pulse facilitation (interstimulus interval of 50 ms), suggesting that neither presynaptic transmitter release or activity of interneurons in vivo are affected. The effects of Ab on LTP are therefore likely to be mediated via a postsynaptic mechanism. This in vivo model of LTP is extremely sensitive to Ab-peptides that can impair LTP in a time([25–35]) and concentration-dependent manner ([25–35] and [35–25]). These effects of Ab-peptides may then contribute to the cognitive deficits associated with Alzheimer’s disease.