Disruption of neuronal signaling by soluble beta-amyloid has been implicated in deficits in short-term recall in the early stages of Alzheimer's disease. One potential target for beta-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 beta-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 beta-amyloid on terminals isolated from mice harboring either beta2 or alpha7 nicotinic receptor null mutants (knockouts). Average pre-synaptic responses to beta-amyloid in hippocampal terminals of alpha7 knockout mice were unchanged, whereas responses in hippocampal terminals from beta2 knockout mice were strongly attenuated. In contrast, pre-synaptic responses to soluble beta-amyloid were strongly attenuated in cortical terminals from alpha7 knockout mice but were moderately attenuated in cortical terminals from beta2 knockout mice. The latter responses, having distinct kinetics, were completely blocked by alpha-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 beta-amyloid, and also indicated differential neuromodulation by beta-amyloid of synapses in hippocampus and cortex.