Down syndrome (DS; trisomy 21) is the most common genetic cause of mental retardation, affecting about one in every 800 individuals. About 60% of the genes on human chromosome 21 are present on mouse chromosome 16 and mouse trisomy 16 (Ts16) has been studied as a potential model for DS. Cultured hippocampal neurons from embryonic Ts16 mice undergo accelerated death by apoptosis in vitro compared with neurons from Euploid littermates. The purpose of this study was to determine the molecular mechanism underlying this accelerated death. Brain-derived Neurotrophic Factor (BDNF), acting through its receptor, trkB, is a well-described autocrine survival factor for hippocampal neurons. BDNF binding to trkB initiates receptor dimerization, autophosphorylation, and activation of several signaling pathways, including AKT and ERK, two signal transduction molecules whose activation by phosphorylation promotes cell survival. To test whether BDNF promoted autocrine survival in Euploid and Ts16 neuronal cultures, endogenous BDNF was removed from the culture medium using a trkB-IgG fusion protein. In the absence of BDNF, Euploid survival was decreased two- to three-fold, similar to control Ts16 survival levels. Survival of the Ts16 neurons was not affected by the removal of BDNF, indicating an absence of autocrine survival signaling by BDNF. Moreover, unlike Euploid neurons, BDNF did not prevent death induced by serum supplement withdrawal in Ts16 neurons. Both Euploid and Ts16 neurons express full-length, catalytically-active trkB, however Ts16 neurons over-express a truncated, kinase-inactive isoform of trkB, which could act as a dominant negative inhibitor of survival signaling. To test whether the over-expression of truncated trkB in Ts16 neurons was the cause of their inability to respond to BDNF, Ts16 neurons were infected with replication-incompetent adenoviruses containing DNA for full-length trkB. The over-expression of full-length trkB in Ts16 neurons completely restored BDNF-mediated survival signaling. In parallel experiments, the over-expression of truncated trkB in Euploid neurons abolished their responsiveness to BDNF, rendering them indistinguishable from Ts16 control neurons. Thus, Ts16 neurons have a selective BDNF survival defect, probably caused by excess truncated trkB, which can be corrected by increasing the levels of full-length trkB.