The medium spiny neuron is the predominant striatal neuronal subtype. The striatum, a participant in motor and cognitive functions, is a site of pathophysiology in prevalent neuropsychiatric diseases and is the target of many currently utilized pharmacologic agents. DARPP-32, a dopamine and cyclic AMP-regulated phosphoprotein, is a widely-used marker of mature striatal medium-sized neurons, but the molecules regulating DARPP-32 transcription have not been identified. We show that a null mutation in the mouse brain-derived neurotrophic factor gene leads to decreased DARPP-32 immunoreactivity in striatal medium spiny neurons at birth and postnatal day 10. Striatal DARPP-32 messenger RNA and protein are decreased relative to wild-type littermate controls. In densely plated (1 x 10(6) cells/cm2) primary cultures derived from the ganglionic eminences, addition of brain-derived neurotrophic factor (100 ng/ml) to defined media results in a greater than 3-fold increase in the number of DARPP-32-immunopositive cells after 12 h and greater than 4-fold (P<0.005) after 24 h. The increase in DARPP-32-immunopositivity is abolished by the addition of 2 microg/ml actinomycin D without a significant effect on cell viability. These data suggest that brain-derived neurotrophic factor directly or indirectly regulates DARPP-32 transcription in medium spiny neurons. This is the first demonstration of transcriptional regulation of DARPP-32, and the first evidence of a forebrain abnormality in a newborn neurotrophin "knockout" mouse.