We report on the characterization of the novel rat brain protein dendrin which is encoded by the brain-specific transcript 464. On immunoblots, two protein variants (81 kD, 89 kD) were identified in cytosolic and membraneous protein fractions. The variants are most abundant in the hippocampus, notably in apical dendrites of CA1 pyramidal cells. Dendritic and perikaryal immunolabelling is apparent in neurons of the cerebral cortex, dentate gyrus, subiculum, amygdala, and preoptic areas. In cortical and hippocampal dendrites, electron-dense immunoreaction is associated with the endoplasmic reticulum, the plasma membrane, and spine heads. An association of dendrin with polyribosomes and the presence of its mRNA in dendrites both provide evidence for dendritic mRNA translation. In the rat forebrain, dendrin expression is altered after an extended period of wakefulness. Twenty-four-hour sleep deprivation decreases the mRNA and protein concentrations of both variants in subcortical forebrain plus midbrain areas by 24 +/- 11% (P < 0.05) and 40 +/- 14% (P < 0.1), respectively, as measured relative to beta-actin mRNA and neural actin. In the cerebral cortex and hippocampus, the relative mRNA level remains unchanged whereas the cortical protein concentration is reduced by 42 +/- 10% (P < 0.05). Thus, dendrin belongs to a new class of dendritic proteins whose expression is differentially modulated by prolonged behavioral activity.