Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington's disease

Joshua L. Plotkin, Michelle Day, Jayms D. Peterson, Zhong Xie, Geraldine J. Kress, Igor Rafalovich, Jyothisri Kondapalli, Tracy S. Gertler, Marc Flajolet, Paul Greengard, Mihaela Stavarache, Michael G. Kaplitt, Jim Rosinski, C. Savio Chan, D. James Surmeier

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. The debilitating choreic movements that plague HD patients have been attributed to striatal degeneration induced by the loss of cortically supplied brain-derived neurotrophic factor (BDNF). Here, we show that in mouse models of early symptomatic HD, BDNF delivery to the striatum and its activation of tyrosine-related kinase B (TrkB) receptors were normal. However, in striatal neurons responsible for movement suppression, TrkB receptors failed to properly engage postsynaptic signaling mechanisms controlling the inductionof potentiation at corticostriatal synapses. Plasticity was rescued by inhibiting p75 neurotrophin receptor(p75NTR) signaling or its downstream targetphosphatase-and-tensin-homolog-deleted-on-chromosome-10 (PTEN). Thus, corticostriatal synaptic dysfunction early in HD is attributable to a correctable defect in the response to BDNF, not its delivery.

Original languageEnglish
Pages (from-to)178-188
Number of pages11
JournalNeuron
Volume83
Issue number1
DOIs
StatePublished - Jul 2 2014

Fingerprint Dive into the research topics of 'Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington's disease'. Together they form a unique fingerprint.

  • Cite this

    Plotkin, J. L., Day, M., Peterson, J. D., Xie, Z., Kress, G. J., Rafalovich, I., Kondapalli, J., Gertler, T. S., Flajolet, M., Greengard, P., Stavarache, M., Kaplitt, M. G., Rosinski, J., Chan, C. S., & Surmeier, D. J. (2014). Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington's disease. Neuron, 83(1), 178-188. https://doi.org/10.1016/j.neuron.2014.05.032