Impaired TrkB Receptor Signaling Underlies Corticostriatal Dysfunction in Huntington’s Disease
Copyright policy )Impaired TrkB Receptor Signaling Underlies Corticostriatal Dysfunction in Huntington’s Disease
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.
- Rockefeller University United States
- Northwestern University United States
- CHDI Foundation United States
- Cornell University United States
Cerebral Cortex, Neuroscience(all), Mice, Transgenic, Corpus Striatum, Mice, Inbred C57BL, Disease Models, Animal, Mice, Huntington Disease, Organ Culture Techniques, Animals, Receptor, trkB, Gene Knock-In Techniques, Signal Transduction
Cerebral Cortex, Neuroscience(all), Mice, Transgenic, Corpus Striatum, Mice, Inbred C57BL, Disease Models, Animal, Mice, Huntington Disease, Organ Culture Techniques, Animals, Receptor, trkB, Gene Knock-In Techniques, Signal Transduction
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