α7 Nicotinic acetylcholine receptor as a target to rescue deficit in hippocampal LTP induction in β-amyloid infused rats

Ling Chen, Kiyofumi Yamada, Toshitaka Nabeshima, Masahiro Sokabe

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Continuous intracerebroventricular infusion of β-amyloid peptide 1-40 (Aβ(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. β-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 Aβ-infused brain. Throughout this study, an effort was made to address whether the α7 nicotinic acetylcholine receptor (α7nAChR), which is believed to be a primary target of Aβ [Wang, H.Y., Lee, D.H., Davis, C.B., Shank, R.P., 2000a. Amyloid peptide Aβ (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 Aβ-infused rats. First, we found that Aβ-infusion markedly depressed the response of α7nAChR to a selective α7nAChR agonist [3-(2,4-dimethoxybenzylidene)-anabaseine] (DMXB). Second, blockade of α7nAChR with either methyllycaconitine (MLA) or α-bungarotoxin (α-BTX) in control rats inhibited LTP induction, suggesting that the activation of α7nAChR is required for LTP induction. Finally, pre-treatment of the slices from Aβ-infused rats with 10 μM DMXB rescued CA1 synapses from the deficit in LTP and PPF. These results suggest that Aβ-impaired LTP and PPF arise as a consequence of dysfunctional α7nAChR, and that α7nAChR may be an important target to help ameliorate AD patient cognitive deficits.

Original languageEnglish
Pages (from-to)254-268
Number of pages15
JournalNeuropharmacology
Volume50
Issue number2
DOIs
Publication statusPublished - 01-02-2006

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Long-Term Potentiation
Nicotinic Receptors
Amyloid
Neuronal Plasticity
Synapses
Alzheimer Disease
Animal Models
Intraventricular Infusions
Amyloidogenic Proteins
Bungarotoxins
Cholinergic Agonists
Synaptic Transmission
Cholinergic Agents
Hippocampus
Learning
Peptides
Brain

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

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title = "α7 Nicotinic acetylcholine receptor as a target to rescue deficit in hippocampal LTP induction in β-amyloid infused rats",
abstract = "Continuous intracerebroventricular infusion of β-amyloid peptide 1-40 (Aβ(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. β-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 Aβ-infused brain. Throughout this study, an effort was made to address whether the α7 nicotinic acetylcholine receptor (α7nAChR), which is believed to be a primary target of Aβ [Wang, H.Y., Lee, D.H., Davis, C.B., Shank, R.P., 2000a. Amyloid peptide Aβ (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 Aβ-infused rats. First, we found that Aβ-infusion markedly depressed the response of α7nAChR to a selective α7nAChR agonist [3-(2,4-dimethoxybenzylidene)-anabaseine] (DMXB). Second, blockade of α7nAChR with either methyllycaconitine (MLA) or α-bungarotoxin (α-BTX) in control rats inhibited LTP induction, suggesting that the activation of α7nAChR is required for LTP induction. Finally, pre-treatment of the slices from Aβ-infused rats with 10 μM DMXB rescued CA1 synapses from the deficit in LTP and PPF. These results suggest that Aβ-impaired LTP and PPF arise as a consequence of dysfunctional α7nAChR, and that α7nAChR may be an important target to help ameliorate AD patient cognitive deficits.",
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α7 Nicotinic acetylcholine receptor as a target to rescue deficit in hippocampal LTP induction in β-amyloid infused rats. / Chen, Ling; Yamada, Kiyofumi; Nabeshima, Toshitaka; Sokabe, Masahiro.

In: Neuropharmacology, Vol. 50, No. 2, 01.02.2006, p. 254-268.

Research output: Contribution to journalArticle

TY - JOUR

T1 - α7 Nicotinic acetylcholine receptor as a target to rescue deficit in hippocampal LTP induction in β-amyloid infused rats

AU - Chen, Ling

AU - Yamada, Kiyofumi

AU - Nabeshima, Toshitaka

AU - Sokabe, Masahiro

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AB - Continuous intracerebroventricular infusion of β-amyloid peptide 1-40 (Aβ(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. β-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 Aβ-infused brain. Throughout this study, an effort was made to address whether the α7 nicotinic acetylcholine receptor (α7nAChR), which is believed to be a primary target of Aβ [Wang, H.Y., Lee, D.H., Davis, C.B., Shank, R.P., 2000a. Amyloid peptide Aβ (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 Aβ-infused rats. First, we found that Aβ-infusion markedly depressed the response of α7nAChR to a selective α7nAChR agonist [3-(2,4-dimethoxybenzylidene)-anabaseine] (DMXB). Second, blockade of α7nAChR with either methyllycaconitine (MLA) or α-bungarotoxin (α-BTX) in control rats inhibited LTP induction, suggesting that the activation of α7nAChR is required for LTP induction. Finally, pre-treatment of the slices from Aβ-infused rats with 10 μM DMXB rescued CA1 synapses from the deficit in LTP and PPF. These results suggest that Aβ-impaired LTP and PPF arise as a consequence of dysfunctional α7nAChR, and that α7nAChR may be an important target to help ameliorate AD patient cognitive deficits.

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