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Defining pre‐synaptic nicotinic receptors regulated by beta amyloid in mouse cortex and hippocampus with receptor null mutants
Author(s) -
Mehta Tejal K.,
Dougherty John J.,
Wu Jianlin,
Choi Catherine H.,
Khan Ghous M.,
Nichols Robert A.
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06070.x
Subject(s) - nicotinic agonist , neuroscience , ganglion type nicotinic receptor , alpha 4 beta 2 nicotinic receptor , knockout mouse , hippocampus , hippocampal formation , receptor , biology , amyloid beta , chemistry , microbiology and biotechnology , nicotinic acetylcholine receptor , biochemistry , peptide
Disruption of neuronal signaling by soluble β‐amyloid has been implicated in deficits in short‐term recall in the early stages of Alzheimer’s disease. One potential target for β‐amyloid is the synapse, with evidence for differential interaction with both pre‐ and post‐synaptic elements. Our previous work revealed an agonist‐like action of soluble β‐amyloid (pM to nM) on isolated pre‐synaptic terminals to increase [Ca 2+ ]i, with apparent involvement of pre‐synaptic nicotinic receptors. To directly establish the role of nicotinic receptors in pre‐synaptic Ca 2+ regulation, we investigated the pre‐synaptic action of β‐amyloid on terminals isolated from mice harboring either β2 or α7 nicotinic receptor null mutants (knockouts). Average pre‐synaptic responses to β‐amyloid in hippocampal terminals of α7 knockout mice were unchanged, whereas responses in hippocampal terminals from β2 knockout mice were strongly attenuated. In contrast, pre‐synaptic responses to soluble β‐amyloid were strongly attenuated in cortical terminals from α7 knockout mice but were moderately attenuated in cortical terminals from β2 knockout mice. The latter responses, having distinct kinetics, were completely blocked by α‐bungarotoxin. The use of receptor null mutants thus permitted direct demonstration of the involvement of specific nicotinic receptors in pre‐synaptic Ca 2+ regulation by soluble β‐amyloid, and also indicated differential neuromodulation by β‐amyloid of synapses in hippocampus and cortex.