title: Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington's disease.
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 induction of potentiation at corticostriatal synapses. Plasticity was rescued by inhibiting p75 neurotrophin receptor (p75NTR) signaling or its downstream target phosphatase-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.
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Plotkin
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Day
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Jayms D
authors.initials: JD
authors.lastname: Peterson
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Geraldine J
authors.initials: GJ
authors.lastname: Kress
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Rafalovich
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Jyothisri
authors.initials: J
authors.lastname: Kondapalli
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Tracy S
authors.initials: TS
authors.lastname: Gertler
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Flajolet
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.affiliation: Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10028, USA.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Stavarache
authors.affiliation: Department of Neurological Surgery, Weill Cornell Medical College, New York, NY 10028, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kaplitt
authors.affiliation: CHDI Management/CHDI Foundation, Princeton, NJ 08540, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Rosinski
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: C Savio
authors.initials: CS
authors.lastname: Chan
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: j-surmeier@northwestern.edu.
authors.forename: D James
authors.initials: DJ
authors.lastname: Surmeier
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology*; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D020813:Receptor, trkB