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

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 transgenic HD mice. 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 (InsP 3 R1) and increases its sensitivity to activation by InsP 3 . We now report that the resulting increase in steady-state InsP 3 R1 activity reduces endoplasmic reticulum (ER) Ca 2ϩ levels. Depletion of ER Ca 2ϩ leads to overactivation of the neuronal store-operated Ca 2ϩ 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 InsP 3 R1 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.

Inositol 1,4,5‐trisphosphate receptors and neurodegenerative disorders

“…These data also supports potential use of IC10 peptide as a novel HD therapeutic agent [79]. In further experiments, it was shown that chronically enhanced calcium leakage from YAC128 MSN ER caused a reduction in the ER calcium level and led to increased stromal interaction molecule 2-mediated store-operated calcium entry, and that resulted in the MSN spine loss both in vitro and in vivo [80].…”

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice

“…Mutant HTT (mHTT) has been shown to disrupt a number of cellular and molecular processes that are thought to contribute collectively to clinical manifestations of the disease. These include transcriptional dysfunction (1,2), deficits in trophic support (2)(3)(4), and imbalances in neurotransmitter levels and signaling (5,6) as well as aberrant calcium handling by synaptic (7,8), ER (7,8), and mitochondrial pathways (9).…”

STIM2 regulates AMPA receptor trafficking and plasticity at hippocampal synapses

“…Recent studies, however, reported SOCE responses in dendritic spines 8,9 , small dendritic protrusions at the tip of which terminate most excitatory inputs. Synaptic SOCE is STIM2-dependent, has been linked to spine maturation and is dysregulated in mouse models of Alzheimer's and Huntington's disease [8][9][10][11] .…”