Integrins are heterodimeric transmembrane cell adhesion receptors that are essential for a wide range of biological functions via cell-matrix and cell-cell interactions. Recent studies have provided evidence that some of the subunits in the integrin family are involved in synaptic and behavioral plasticity. To further understand the role of integrins in the mammalian central nervous system, we generated a postnatal forebrain and excitatory neuron-specific knockout of alpha8-integrin in the mouse. Behavioral studies showed that the mutant mice are normal in multiple hippocampal-dependent learning tasks, including a T-maze, non-match-to-place working memory task for which other integrin subunits like alpha3- and beta1-integrin are required. In contrast, mice mutant for alpha8-integrin exhibited a specific impairment of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses, whereas basal synaptic transmission, paired-pulse facilitation and long-term depression (LTD) remained unaffected. Because LTP is also impaired in the absence of alpha3-integrin, our results indicate that multiple integrin molecules are required for the normal expression of LTP, and different integrins display distinct roles in behavioral and neurophysiological processes like synaptic plasticity.