Defining pre-synaptic nicotinic receptors regulated by beta amyloid in mouse cortex and hippocampus with receptor null mutants

• Published in: Journal of neurochemistry Vol. 109; no. 5; pp. 1452 - 1458
• Main Authors: Mehta, Tejal K, Dougherty, John J, Wu, Jianlin, Choi, Catherine H, Khan, Ghous M, Nichols, Robert A
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.06.2009; Blackwell Publishing Ltd; Wiley-Blackwell
• Subjects: Adult and adolescent clinical studies; alpha7 Nicotinic Acetylcholine Receptor; Alzheimer's disease; Amyloid beta-Peptides - pharmacology; Animals; Biochemistry; Biological and medical sciences; Bungarotoxins - pharmacology; Calcium - metabolism; calcium regulation; Cerebral Cortex - cytology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Hippocampus - cytology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurology; Nicotine - pharmacology; Nicotinic Agonists - pharmacology; nicotinic receptors; Organic mental disorders. Neuropsychology; Peptide Fragments - pharmacology; pre-synaptic terminal; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Receptors, Nicotinic - deficiency; Receptors, Nicotinic - physiology; Rodents; Signal transduction; Synaptosomes - drug effects; Synaptosomes - physiology; Short term; Calcium; Alzheimer disease; Central nervous system; Early stage; pre-synaptic terminal; Encephalon; Signal transduction; Cholinergic receptor; α7 nicotinic receptor; Degenerative disease; Nicotinic receptor; Biological receptor; Nervous system diseases; calcium regulation; Extracellular calcium-sensing receptor; Interaction; Rodentia; Cerebral disorder; Vertebrata; Synapse; Mammalia; Mouse; Central nervous system disease; nicotinic receptors; Kinetics; Disruption; Hippocampus
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2009.06070.x

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 [Ca²⁺]i, with apparent involvement of pre-synaptic nicotinic receptors. To directly establish the role of nicotinic receptors in pre-synaptic Ca²⁺ 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 Ca²⁺ regulation by soluble β-amyloid, and also indicated differential neuromodulation by β-amyloid of synapses in hippocampus and cortex.