The neurotrophin, brain derived neurotrophic factor (BDNF), exerts multiple effects on the development and maintenance of the nervous system, including regulating synaptic plasticity and promoting neuron survival. Here we report the selective failure of BDNF-dependent survival in cultured hippocampal neurons from the trisomy 16 (Ts16) mouse, an animal model of Down syndrome. This failure is accompanied by overexpression of a truncated, kinase-deficient isoform (T1) of the BDNF receptor tyrosine receptor kinase B (trkB). Adenovirus-mediated introduction of exogenous full-length trkB into Ts16 neurons fully restored BDNF-dependent survival, whereas exogenous truncated trkB expression in normal, euploid neurons reproduced the Ts16 BDNF signaling failure. Thus, the failure of Ts16 neurons to respond to BDNF is caused by dysregulation of trkB isoform expression. Such a neurotrophin signaling defect could contribute to developmental and degenerative disorders of the nervous system.