Enhanced store-operated calcium entry leads to striatal synaptic loss in a huntington’s disease mouse model

Jun Wu, Daniel A. Ryskamp, Xia Liang, Polina Egorova, Olga Zakharova, Gene Hung, Ilya Bezprozvanny

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

In Huntington’s disease (HD), mutant Huntingtin (mHtt) protein causes striatal neuron dysfunction, synaptic loss, and eventual neurodegeneration. To understand the mechanisms responsible for synaptic loss in HD, we developed a corticostriatal coculture model that features age-dependent dendritic spine loss in striatal medium spiny neurons (MSNs) from YAC128 transgenicHDmice. Age-dependent spine loss was also observed in vivo in YAC128 MSNs. To understand the causes of spine loss in YAC128 MSNs, we performed a series of mechanistic studies. We previously discovered that mHtt protein binds to type 1 inositol (1,4,5)-trisphosphate receptor (InsP3R1) and increases its sensitivity to activation by InsP3. We now report that the resulting increase in steady-state InsP3R1 activity reduces endoplasmic reticulum (ER) Ca2 + levels. Depletion of ER Ca2 + leads to overactivation of the neuronal store-operated Ca2 + entry (nSOC) pathway in YAC128 MSN spines. The synaptic nSOC pathway is controlled by the ER resident protein STIM2. We discovered that STIM2 expression is elevated in aged YAC128 striatal cultures and in YAC128 mouse striatum. Knock-down of InsP3R1 expression by antisense oligonucleotides or knock-down or knock-out of STIM2 resulted in normalization of nSOC and rescue of spine loss in YAC128 MSNs. The selective nSOC inhibitor EVP4593 was identified in our previous studies. We now demonstrate that EVP4593 reduces synaptic nSOC and rescues spine loss in YAC128 MSNs. Intraventricular delivery of EVP4593 in YAC128 mice rescued age-dependent striatal spine loss in vivo. Our results suggest EVP4593 and other inhibitors of the STIM2-dependent nSOC pathway as promising leads for HD therapeutic development.

Original languageEnglish (US)
Pages (from-to)125-141
Number of pages17
JournalJournal of Neuroscience
Volume36
Issue number1
DOIs
StatePublished - Jan 6 2016

Keywords

  • Calcium
  • Huntingtin
  • Imaging
  • Synapse
  • Transgenic

ASJC Scopus subject areas

  • Neuroscience(all)

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