BDNF stimulates expression, activity and release of tissue-type plasminogen activator in mouse cortical neurons

Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor involved in neuronal development and synaptic plasticity. Although the physiological effects of BDNF have been examined in detail, target proteins which mediat e its actions remain largely unknown. Here, we report that BDNF stimulates the expression of tissue-type plasminogen activator (tPA) in primary cultur es of cortical neurons in a time- and concentration-dependent manner. Among the other members of the neurotrophin family, neurotrophin-4 (NT-4) and to a lesser extent neurotrophin-3 (NT-3) also increased tPA mRNA expression, while nerve growth factor (NGF) was devoid of any effect. Induction of tPA expression by BDNF is accompanied by an increase in the proteolytic activit y of tPA associated with cortical neurons and a release of tPA into the ext racellular space. Release of tPA induced by BDNF depends on extracellular C a2+ since it is markedly reduced in the presence of ethylene glycol-bis(bet a-aminoethylether)-N,N,N',N'-acid (EGTA). Upregulation of tPA expression by BDNF is followed by the induction of plasminogen activator inhibitor 2 (PA I-2), an inhibitor of tPA. Together these results suggest that activation o f tPA by BDNF may contribute to structural changes associated with neuronal development or synaptic plasticity.