Enhanced Store-Operated Calcium Entry Leads to Striatal Synaptic Loss in a Huntington's Disease Mouse Model

• DOI: 10.1523/jneurosci.1038-15.2016
• Publication Date: 2016-01-06T17:28:13Z
• Authors: Jun Wu; Daniel A. Ryskamp; Xia Liang; Polina Egorova; Olga Zakharova; Gene Hung; Ilya Bezprozvanny
• Keywords: Medium spiny neuron

In Huntington's disease (HD), mutant Huntingtin (mHtt) protein causes striatal neuron dysfunction, synaptic loss, and eventual neurodegeneration. To understand the mechanisms responsible for loss in HD, we developed a corticostriatal coculture model that features age-dependent dendritic spine medium spiny neurons (MSNs) from YAC128 transgenic HD mice. Age-dependent was also observed vivo MSNs. of MSNs, performed series mechanistic studies. We previously discovered mHtt binds to type 1 inositol (1,4,5)-trisphosphate receptor (InsP 3 R1) increases its sensitivity activation by InsP . now report resulting increase steady-state R1 activity reduces endoplasmic reticulum (ER) Ca 2+ levels. Depletion ER leads overactivation neuronal store-operated entry (nSOC) pathway MSN spines. The nSOC is controlled resident STIM2. STIM2 expression elevated aged cultures mouse striatum. Knock-down antisense oligonucleotides or knock-down knock-out resulted normalization rescue selective inhibitor EVP4593 identified our previous demonstrate rescues Intraventricular delivery mice rescued Our results suggest other inhibitors STIM2-dependent as promising therapeutic development. SIGNIFICANCE STATEMENT (HD) early dysfunction neurodegeneration through poorly understood mechanisms. here cocultures prepared feature mirroring This finding establishes system studies instability HD. use it sensitization receptors mHtt, which depletes calcium, contributes synaptotoxic enhancement calcium (SOC) entry. Treatment with EVP4593, neuroprotective SOC channels, both vitro These enhanced HD-afflicted