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Mossy cell synaptic dysfunction causes memory imprecision via miR-128 inhibition of STIM2 in Alzheimer's disease
Manfei Deng1,2, Qingping Zhang1,2, Zhuoze Wu1,2
1Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
Recently, we have reported that dentate mossy cells (MCs) control memory precision via directly and functionally innervating local somatostatin (SST) inhibitory interneurons. Here, we report a discovery that dysfunction of synaptic transmission between MCs and SST cells causes memory imprecision in a mouse model of early Alzheimer's disease (AD). Single-cell RNA sequencing reveals that miR-128 that binds to a 3'UTR of STIM2 and inhibits STIM2 translation is increasingly expressed in MCs from AD mice. Silencing miR-128 or disrupting miR-128 binding to STIM2 evokes STIM2 expression, restores synaptic function, and rescues memory imprecision in AD mice. Comparable findings are achieved by directly engineering MCs with the expression of STIM2. This study unveils a key synaptic and molecular mechanism that dictates how memory maintains or losses its details and warrants a promising target for therapeutic intervention of memory decays in the early stage of AD.
Insights
Dysfunction in memory circuits causes imprecision in Alzheimer's disease (AD) models. Restoring STIM2 expression in dentate mossy cells (MCs) rescues synaptic function and improves memory precision in early AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Dentate mossy cells (MCs) are crucial for memory precision by innervating somatostatin (SST) interneurons.
- Early Alzheimer's disease (AD) is associated with memory imprecision, but the underlying synaptic and molecular mechanisms remain unclear.
Purpose of the Study:
- To investigate the synaptic and molecular mechanisms underlying memory imprecision in early AD.
- To identify potential therapeutic targets for memory deficits in AD.
Main Methods:
- Utilized a mouse model of early Alzheimer's disease (AD).
- Employed single-cell RNA sequencing to analyze gene expression in MCs.
- Investigated the role of miR-128 and STIM2 in synaptic function and memory.
- Manipulated miR-128 expression and STIM2 levels in MCs.
Main Results:
- MCs dysfunction and impaired synaptic transmission to SST cells contribute to memory imprecision in AD mice.
- miR-128 expression is upregulated in MCs from AD mice, inhibiting STIM2 translation.
- Silencing miR-128 or increasing STIM2 expression restores synaptic function and rescues memory imprecision.
- Directly enhancing STIM2 expression in MCs also ameliorates memory deficits.
Conclusions:
- A miR-128/STIM2 pathway in MCs is critical for maintaining memory precision.
- Dysregulation of this pathway contributes to memory deficits in early AD.
- Targeting the miR-128/STIM2 pathway offers a potential therapeutic strategy for early AD memory loss.
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