alpha7 Nicotinic Acetylcholine Receptor as a Target to Rescue Deficit in Hippocampal LTP Induction in Beta-Amyloid Infused Rats

Neuropharmacology. 2006 Feb;50(2):254-68. doi: 10.1016/j.neuropharm.2005.09.018. Epub 2005 Dec 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / pharmacology*
  • Animals
  • Benzylidene Compounds / pharmacology
  • Data Interpretation, Statistical
  • Electric Stimulation
  • Electrophysiology
  • Hippocampus / drug effects*
  • In Vitro Techniques
  • Long-Term Potentiation / drug effects*
  • Male
  • Membrane Potentials / drug effects
  • Nicotinic Agonists / pharmacology
  • Nicotinic Antagonists / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Nicotinic / drug effects*
  • Receptors, Nicotinic / metabolism
  • alpha7 Nicotinic Acetylcholine Receptor


  • Amyloid beta-Peptides
  • Benzylidene Compounds
  • Chrna7 protein, rat
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Pyridines
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • nicotinic receptor alpha4beta2
  • 3-(2,4-dimethoxybenzylidene)anabaseine