alpha7 Nicotinic acetylcholine receptor as a target to rescue deficit in hippocampal LTP induction in beta-amyloid infused rats.
Continuous intracerebroventricular infusion of beta-amyloid peptide 1-40 (Abeta(1-40)) in animal models induces learning and memory impairment associated with dysfunction of the cholinergic neuronal system, which has been considered to be a pathological model of Alzheimer's disease [Nitta, A., Itoh, A., Hasegawa, T., Nabeshima, T., 1994. Beta-amyloid protein-induced Alzheimer's disease animal model. Neurosci. Lett. 170, 63-66.]. Here, using a real-time optical recording technique, we demonstrate that basal synaptic transmission and several forms of synaptic plasticity, including long-term potentiation (LTP), post-tetanic potentiation (PTP) and paired-pulse facilitation (PPF) are deficient at the Schaffer collateral-CA1 synapse in hippocampal slices from Abeta-infused brain. Throughout this study, an effort was made to address whether the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), which is believed to be a primary target of Abeta [Wang, H.Y., Lee, D.H., Davis, C.B., Shank, R.P., 2000a. Amyloid peptide Abeta (1-42) binds selectively and with picomolar affinity to alpha 7 nicotinic acetylcholine receptors. J. Neurochem. 75, 1155-1161.], is responsible for the deficits in synaptic plasticity observed in the Abeta-infused rats. First, we found that Abeta-infusion markedly depressed the response of alpha7nAChR to a selective alpha7nAChR agonist [3-(2,4-dimethoxybenzylidene)-anabaseine] (DMXB). Second, blockade of alpha7nAChR with either methyllycaconitine (MLA) or alpha-bungarotoxin (alpha-BTX) in control rats inhibited LTP induction, suggesting that the activation of alpha7nAChR is required for LTP induction. Finally, pre-treatment of the slices from Abeta-infused rats with 10 microM DMXB rescued CA1 synapses from the deficit in LTP and PPF. These results suggest that Abeta-impaired LTP and PPF arise as a consequence of dysfunctional alpha7nAChR, and that alpha7nAChR may be an important target to help ameliorate AD patient cognitive deficits.
Chen
Ling
L
ICORP/SORST Cell Mechanosensing, JST, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Yamada
Kiyofumi
K
Nabeshima
Toshitaka
T
Sokabe
Masahiro
M
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D004558:Electric Stimulation; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; D001597:Benzylidene Compounds; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; C088936:3-(2,4-dimethoxybenzylidene)anabaseine