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

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Huntington's disease (HD) is characterized by mutant Huntingtin (mHtt) protein leading to striatal neuron dysfunction, synaptic loss, and neurodegeneration.
• The precise mechanisms underlying synaptic loss in HD, particularly in medium spiny neurons (MSNs), remain incompletely understood.

Purpose of the Study:

• To elucidate the mechanisms responsible for age-dependent dendritic spine loss in MSNs in the context of HD.
• To investigate the role of the inositol (1,4,5)-trisphosphate receptor (InsP3R1) and store-operated calcium (SOC) entry in HD-related synaptic instability.
• To evaluate the therapeutic potential of targeting the STIM2-dependent neuronal SOC (nSOC) pathway.

Main Methods:

• Development of a corticostriatal coculture model using YAC128 transgenic HD mice exhibiting age-dependent MSN spine loss.
• In vivo assessment of spine loss in YAC128 MSNs.
• Mechanistic studies involving manipulation of InsP3R1 and STIM2 expression (antisense oligonucleotides, knock-down, knock-out).
• Pharmacological intervention using the selective nSOC inhibitor EVP4593, administered in vitro and in vivo (intraventricular delivery).

Main Results:

• Age-dependent dendritic spine loss was observed in MSNs from YAC128 HD mice, both in vitro and in vivo.
• Mutant Huntingtin (mHtt) sensitizes InsP3R1, leading to endoplasmic reticulum (ER) Ca(2+) depletion and subsequent overactivation of the STIM2-dependent nSOC pathway in MSN spines.
• Elevated STIM2 expression was found in aged YAC128 striatal cultures and mouse striatum.
• Inhibition of InsP3R1 or STIM2 normalized nSOC and rescued spine loss in YAC128 MSNs.
• Treatment with EVP4593 reduced synaptic nSOC and rescued spine loss in vitro and in vivo.

Conclusions:

• Enhanced STIM2-dependent neuronal store-operated calcium (nSOC) entry, triggered by mHtt-induced InsP3R1 sensitization and ER calcium depletion, is a key driver of synaptic loss in HD MSNs.
• The selective nSOC inhibitor EVP4593 demonstrates neuroprotective effects, rescuing synaptic deficits in HD models.
• Targeting the STIM2-dependent nSOC pathway represents a promising therapeutic strategy for Huntington's disease.