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.
Highlights
Alzheimer's disease (AD) is the most common cause of brain degeneration characterized by a progressive memory decline and a subsequent loss of broader cognitive functions (Selkoe, 2001; Sisodia & St GeorgeHyslop, 2002)
We have shown that memory is imprecise in a mouse model of early AD and an imprecision of memory is associated with a selective degeneration of mossy cells (MCs) synapses
We have reported that mossy cells (MCs) in the dentate gyrus directly and functionally innervate local somatostatin (SST)-expressing cells and this innervation controls memory precision (Xinyan Li et al, 2019) (Li, X and Huang, X, manuscript submitted).We reasoned that dysfunction of synaptic transmission from MCs to SST cells contributes to memory imprecision in an early stage of AD
Summary
Alzheimer's disease (AD) is the most common cause of brain degeneration characterized by a progressive memory decline and a subsequent loss of broader cognitive functions (Selkoe, 2001; Sisodia & St GeorgeHyslop, 2002). Recent studies indicate that memory loss is caused by synaptic dysfunction rather than neuronal death In APPswe/PSEN1dE9 mice (AD mice) that carry a transgene encoding the 695-amino-acid isoform of the human Aβ precursor protein with the Swedish mutation and a mutant human presenilin 1 (PS1-dE9), which exhibit plaque pathologies similar to those in AD patients, synaptic dysfunctions in the hippocampus, a brain region responsible for learning and memory, reduce the capability of spatial information acquisition (Reiserer, Harrison, Syverud, & McDonald, 2007; Scheff, Price, Schmitt, DeKosky, & Mufson, 2007; Yang et al, 2018). There were three key questions that are yet to be answered: (a) Which of over hundred millions of excitatory synapses in the hippocampus undergo degeneration in the early stage of AD; (b) whether a selective degeneration of certain types of synapses contributes directly to the impairments of memories; and (c) what are the molecular mechanisms underlying degeneration of a specific synapse in the central neurons and whether intervention of this synaptic degeneration is therapeutically effective for AD therapies?
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