Presenilin 1 (PS1) plays a critical role in cleaving amyloid precursor protein (APP) to produce amyloid-beta (Abeta), the primary proteinaceous component of the senile plaques associated with Alzheimer's disease. In addition to mediating the cleavage of APP and a number of other proteins, a growing body of evidence suggests that PS1 also regulates intracellular endoplasmic reticulum calcium levels. Such findings suggest that PS1 activity may modulate neuronal excitability, as well. To address this issue we examined cytosolic intracellular calcium responses in PS1-deficient neurons stimulated by the excitatory amino acid neurotransmitter, glutamate. We found that glutamate-induced intracellular calcium levels were markedly reduced in neurons lacking PS1 (-/-) compared with heterozygous (+/-) and wild-type (+/+) neurons. To prove that PS1 was sufficient to mediate normal glutamate-induced calcium responses, we used a Semliki-forest virus (SFV) vector to express wild-type PS1 in PS1 knock-out neurons. We found that heterologous PS1 expression restored glutamate-evoked calcium responses in PS1-deficient neurons to levels matching non-infected wild-type cells. PS1-deficient neurons infected with SFV directing expression of beta-galactosidase failed to rescue the wild-type phenotype. These results support the idea that normal PS1 activity regulates neuronal responses to neurotransmitter stimulation.