BRAIN-DERIVED NEUROTROPHIC FACTOR REGULATES MATURATION OF THE DARPP-32 PHENOTYPE IN STRIATAL MEDIUM SPINY NEURONS - STUDIES IN-VIVO AND IN-VITRO

The medium spiny neuron is the predominant striatal neuronal subtype.( 18) 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,(5,7) but the molecules regulating DARPP-32 transcription have not been identified. We show t hat a null mutation in the mouse brain-derived neurotrophic factor gen e leads to decreased DARPP-32 immunoreactivity in striatal medium spin y neurons at birth and postnatal day 10. Striatal DARPP-32 messenger R NA and protein are decreased relative to wild-type littermate controls . In densely plated (1 x 10(6) cells/cm(2)) primary cultures derived f rom the ganglionic eminences, addition of brain-derived neurotrophic f actor (100 ng/ml) to defined media results in a greater than 3-fold in crease in the number of DARPP-32-immunopositive cells after 12 h and g reater than 4-fold (P<0.005) after 24 h. The increase in DARPP-32-immu nopositivity is abolished by the addition of 2 mu g/ml actinomycin D w ithout a significant effect on cell viability. These data suggest that brain-derived neurotrophic factor directly or indirectly regulates DA RPP-32 transcription in medium spiny neurons. This is the first demons tration of transcriptional regulation of DARPP-32, and the first evide nce of a forebrain abnormality in a newborn neurotrophin ''knockout'' mouse. (C) 1997 IBRO.