The influence of neurotrophins on GABAergic properties of developing striatal neurons was investigated both in vivo and in vitro. Brain-derived neurotrophic factor (BDNF) specifically elevated cellular GABA content in striatal culture without altering neuronal survival. Neurotrophin-5 produced a similar effect on GABA, but nerve growth factor and neurotrophin-3 had no effect. An increase in GABA content in the striatum was also observed following BDNF injections into the cerebroventricle of neonatal rats. The increase of GABA levels in culture mainly resulted from an increase in holoenzyme activity of the GABA synthetic enzyme glutamic acid decarboxylase (GAD) and elevation of GABA uptake activity. In BDNF-treated striatal cultures, the newly differentiated neurons extended elaborate neurites and exhibited strong GAD immunoreactivity. These alterations were presumably caused by the upregulation of mRNA encoding GAD67 and the neuronal GABA transporter GAT-1. BDNF treatment also promoted other phenotypic differentiation of striatal neurons: BDNF increased the frequency of parvalbumin-immunoreactive neurons and calbindin-immunoreactive neurons and neuropeptide content for neuropeptide Y and somatostatin. These observations suggest that neurotrophins may contribute to phenotypic differentiation of GABAergic neurons in the developing striatum.