Integrins regulate cytoplasmic calcium levels ([Ca(2+)]i) in various cell types but information on activities in neurons is limited. The issue is of current interest because of the evidence that both integrins and changes in [Ca(2+)]i are required for Long-Term Potentiation. Accordingly, the present studies evaluated integrin ligand effects in cortical neurons. Integrin ligands or alpha5beta1 integrin activating antisera rapidly increased [Ca(2+)]i with effects greater in glutamatergic than GABAergic neurons, absent in astroglia, and blocked by beta1 integrin neutralizing antisera and the tyrosine kinase antagonist genistein. Increases depended upon extracellular calcium and intracellular store release. Ligand-induced effects were reduced by voltage-sensitive calcium channel and NMDA receptor antagonists, but blocked by tetrodotoxin or AMPA receptor antagonists. These results indicate that integrin ligation triggers AMPA receptor/depolarization-dependent calcium influx followed by intracellular store release and suggest the possibility that integrin modulation of activity-induced changes in [Ca(2+)]i contributes importantly to lasting synaptic plasticity in forebrain neurons.