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

doi:10.1016/j.neuron.2014.05.032

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

163 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(p75_NTR) 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 language	English (US)
Pages (from-to)	178-188
Number of pages	11
Journal	Neuron
Volume	83
Issue number	1
DOIs	https://doi.org/10.1016/j.neuron.2014.05.032
State	Published - Jul 2 2014

Funding

The Cure Huntington’s Disease Initiative Foundation (D.J.S.), the JPB Foundation (M.G.K., D.J.S., P.G.), the Fisher Center for Alzheimer’s Research Foundation (P.G.), and the NIH (NS034696 and MH074866 to D.J.S.; NS067414 to M.G.K.) supported this work. We thank Dr. D. Wokosin, Dr. E. Ilijic, S. Ulrich, and K. Saporito for technical assistance.

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2014.05.032

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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

@article{b3a0a12f1c6f452a9c932df256ea3786,

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 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.",

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

note = "Funding Information: The Cure Huntington{\textquoteright}s Disease Initiative Foundation (D.J.S.), the JPB Foundation (M.G.K., D.J.S., P.G.), the Fisher Center for Alzheimer{\textquoteright}s Research Foundation (P.G.), and the NIH (NS034696 and MH074866 to D.J.S.; NS067414 to M.G.K.) supported this work. We thank Dr. D. Wokosin, Dr. E. Ilijic, S. Ulrich, and K. Saporito for technical assistance. ",

year = "2014",

month = jul,

day = "2",

doi = "10.1016/j.neuron.2014.05.032",

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Plotkin, JL, Day, M, Peterson, JD, Xie, Z, Kress, GJ, Rafalovich, I, Kondapalli, J, Gertler, TS, Flajolet, M, Greengard, P, Stavarache, M, Kaplitt, MG, Rosinski, J, Chan, CS & Surmeier, DJ 2014, 'Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington's disease', Neuron, vol. 83, no. 1, pp. 178-188. https://doi.org/10.1016/j.neuron.2014.05.032

TY - JOUR

T1 - Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington's disease

AU - Plotkin, Joshua L.

AU - Day, Michelle

AU - Peterson, Jayms D.

AU - Xie, Zhong

AU - Kress, Geraldine J.

AU - Rafalovich, Igor

AU - Kondapalli, Jyothisri

AU - Gertler, Tracy S.

AU - Flajolet, Marc

AU - Greengard, Paul

AU - Stavarache, Mihaela

AU - Kaplitt, Michael G.

AU - Rosinski, Jim

AU - Chan, C. Savio

AU - Surmeier, D. James

N1 - Funding Information: The Cure Huntington’s Disease Initiative Foundation (D.J.S.), the JPB Foundation (M.G.K., D.J.S., P.G.), the Fisher Center for Alzheimer’s Research Foundation (P.G.), and the NIH (NS034696 and MH074866 to D.J.S.; NS067414 to M.G.K.) supported this work. We thank Dr. D. Wokosin, Dr. E. Ilijic, S. Ulrich, and K. Saporito for technical assistance.

PY - 2014/7/2

Y1 - 2014/7/2

N2 - 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.

AB - 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.

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U2 - 10.1016/j.neuron.2014.05.032

DO - 10.1016/j.neuron.2014.05.032

M3 - Article

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AN - SCOPUS:84903627709

SN - 0896-6273

VL - 83

SP - 178

EP - 188

JO - Neuron

JF - Neuron

IS - 1

ER -

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

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