Aberrant miR-339-5p/neuronatin signaling causes prodromal neuronal calcium dyshomeostasis in mutant presenilin mice
Hao-Yu Zou, … , Nan-Jie Xu, Suya Sun
Hao-Yu Zou, … , Nan-Jie Xu, Suya Sun
Published April 15, 2022
Citation Information: J Clin Invest. 2022;132(8):e149160. https://doi.org/10.1172/JCI149160.
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Aberrant miR-339-5p/neuronatin signaling causes prodromal neuronal calcium dyshomeostasis in mutant presenilin mice

Abstract

Mushroom spine loss and calcium dyshomeostasis are early hallmark events of age-related neurodegeneration, such as Alzheimer’s disease (AD), that are connected with neuronal hyperactivity in early pathology of cognitive brain areas. However, it remains elusive how these key events are triggered at the molecular level for the neuronal abnormality that occurs at the initial stage of disease. Here, we identify downregulated miR-339-5p and its upregulated target protein, neuronatin (Nnat), in cortex neurons from the presenilin-1 M146V knockin (PSEN1-M146V KI) mouse model of familial AD (FAD). Inhibition of miR-339-5p or overexpression of Nnat recapitulates spine loss and endoplasmic reticulum calcium overload in cortical neurons with the PSEN1 mutation. Conversely, either overexpression of miR-339-5p or knockdown of Nnat restores spine morphogenesis and calcium homeostasis. We used fiber photometry recording during the object-cognitive process to further demonstrate that the PSEN1 mutant causes defective habituation in neuronal reaction in the retrosplenial cortex and that this can be rescued by restoring the miR-339-5p/Nnat pathway. Our findings thus reveal crucial roles of the miR-339-5p/Nnat pathway in FAD that may serve as potential diagnostic and therapeutic targets for early pathogenesis.

Authors

Hao-Yu Zou, Lin Guo, Bei Zhang, Si Chen, Xin-Rong Wu, Xian-Dong Liu, Xin-Yu Xu, Bin-Yin Li, Shengdi Chen, Nan-Jie Xu, Suya Sun

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Figure 5

Abnormal neuronal activity is associated with the learning process in RSC of KI mice in short-term NORT.

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Abnormal neuronal activity is associated with the learning process in RS...
(A) Schematic of experimental design. Viral injections were performed on 4-week-old mice, and fibers were implanted after a week. For the NORT, mice were exposed to 2 identical objects (object A) for 10 minutes on trial 1 (T1) after habituation. One hour later, one of the objects in A was replaced by a novel object (object B) for trial 2 (T2). (B) Left: schematic of viral injection into the RSC. Right: representative images of viral expression and location of optical fiber tract in RSC. Scale bar: 200 μm. (C–H) Left: exploring time for different objects. n = 18 for each group. Middle: average time courses of Ca2+ signal of different objects were shown for each group. Right: amplitudes of peak Ca2+ signal changes responding to different objects. (C and D) WT and KI control mice. n = 5 for calcium recording in each group. (E and F) Nnat-overexpressed WT and KI mice. n = 5 for calcium recording in each group. (G and H) Nnat-knockdown groups. n = 6 for calcium recording from WT mice injected with AAV-shNnat. n = 5 for calcium recording from KI mice injected with AAV-shNnat. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ****P < 0.0001, paired t test.