The neurotrophins, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin 4/5 (NT-4/5) and nerve growth factor (NGF), were compared for their effects on the survival and differentiation of embryonic rat striatal neurons grown in low-density cultures. Treatment with BDNF for 8 days resulted in a 40% increase in overall neuronal survival, a 3- to 5-fold increase in the number of calbindin-immunoreactive neurons, and an 80% increase in GABA-positive neurons. Treatment with NT-3 or NT-4/5 produced a 2- to 3-fold increase in the number of calbindin-positive neurons and an increase in GABA-positive cell number similar to that induced by BDNF, BDNF treatment produced a striking morphological differentiation of striatal GABAergic neurons, which was characterized by a doubling of the number of neurite branch points, the total area of aborization and the perikaryal area compared to control cultures. All three of these factors increased high-affinity GABA uptake 2-fold. NGF had no effect on any of the parameters examined. Our results show that BDNF, NT-3 and NT-4/5 promote the survival and/or differentiation of calbindin-immunopositive and GABAergic striatal neurons.