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The Journal of Neuroscience, April 1, 2002, 22(7):2571-2578

Failure of Brain-Derived Neurotrophic Factor-Dependent Neuron Survival in Mouse Trisomy 16

Susan G. Dorsey^{1, 3, *}, Linda L. Bambrick^{1, 2, 4, *}, Rita J. Balice-Gordon⁵, and Bruce K. Krueger^{1, 4}

Departments of ¹ Physiology and ² Anesthesiology, University of Maryland School of Medicine, ³ University of Maryland School of Nursing, and ⁴ Program in Neuroscience, University of Maryland Baltimore, Baltimore, Maryland 21201, and ⁵ Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

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.

Key words: adenovirus; BDNF; Down syndrome; neurodegeneration; neuron death; neurotrophin; trisomy 16; trkB

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^* S.G.D. and L.L.B. contributed equally to this work.

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2272571-08$05.00/0

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