Monoclonal antibody Cat-301 recognizes a surface-associated proteoglycan on subsets of neurons in the mammalian CNS (Hockfield and McKay, 1983). The expression of Cat-301 immunoreactivity on Y cells in the cat LGN is sharply reduced by early visual deprivation (Sur et al., 1988). We employed an immunosuppression strategy (Hockfield, 1987) to further study alterations in the expression of experience-dependent molecules. Newborn BALB/c mice were injected with LGN from dark-reared cats to induce a suppression of the immune response to antigens expressed in visually deprived animals. These mice were then immunized with LGN from normal cats to elicit an immune response to antigens with an expression dependent on normal early visual experience. This strategy permitted the generation of monoclonal antibody Cat-304, which recognizes a surface-associated antigen on neuronal cell bodies and proximal dendrites, and which appears histologically identical to Cat- 301. Further analyses show that Cat-304 and Cat-301 recognize different epitopes on the same 680-kDa chondroitin sulfate proteoglycan. We examined the effects of early visual deprivation on Cat-304 immunoreactivity in the LGN and visual cortex of cats. In LGN from normal cats, Cat-304 labels neurons in layers A, A1, and C, in interlaminar zones, and in the medial interlaminar nucleus. In LGN from dark-reared cats, the number of antibody-positive neurons is markedly reduced, and the cross-sectional area of the remaining positive neurons is smaller than normal. In cortical area 17 of normally reared cats, Cat 304-positive neurons are densely distributed in 2 bands, in layers IV and V/VI. Labeled neurons are also present in layers II and III. In area 17 of dark-reared cats, the number of antibody-positive neurons is reduced. The reduction in the number of labeled neurons is most pronounced in layers II/III and V/VI. Antibody-positive neurons are smaller in all cortical layers of dark-reared cats. The changes in the expression of Cat-301 immunoreactivity in dark-reared visual cortex and LGN are identical to those of Cat-304. The laminar differences in the effect of dark rearing on Cat-301 and Cat-304 expression in the visual cortex provides support for the suggestion that layer IV of cortical area 17 may be less susceptible to prolongation of plasticity by dark rearing than layers II/III and V/VI. Further, the biochemical and histological studies reported provide evidence that early visual experience regulates protein expression in the cat LGN and visual cortex.