Actin filaments control cell morphology and are essential to the growth of dendritic spines and the plasticity of hippocampal long-term potentiation (LTP). The length of these filaments is regulated in muscle and nonmuscle cell types by tropomodulins 1-4 (Tmod1-4), a family of proteins that cap the pointed ends of actin filaments. To investigate whether tropomodulins could play a role in synaptic plasticity, learning, memory, or behavior, we created mice lacking Tropomodulin-2 (Tmod2), which is highly expressed in neuronal structures. Tmod2(lacZ-/-) mice are viable and fertile and exhibit no gross morphological or anatomical abnormalities, but behavioral analysis found hyperactivity, reduced sensorimotor gating, and impaired learning and memory. Electrophysiological analysis revealed enhanced LTP in Tmod2(lacZ-/-) mice. These studies suggest that Tmod2 plays a role in behavior, learning, memory, and synaptic plasticity.