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Dcf1 Triggers Dendritic Spine Formation and Facilitates Memory Acquisition

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Abstract

Dendritic spines, a special kind of structure in nerve cells, play a key role in performing cellular function. Structural abnormalities of the dendritic spine may contribute to synaptic dysfunction and have been implicated in memory formation. However, the molecular mechanisms that trigger dendritic spine loss remain unclear. Here, we show that the absence of dendritic cell factor 1 (Dcf1) appeared dendritic spines dysplasia, which in turn leads to the damage of learning and memory; in contrast, enhancing Dcf1 expression rescues dendritic spines morphology and function, indicating a pivotal role of Dcf1 in cellular function. Electrophysiological test indicates that there is a significant reduction in the frequency of miniature excitatory postsynaptic currents in Dcf1−/− knockout (KO) mice. Subsequent to optogenetic ignition, we observed a weaker neuronal activation in Dcf1 KO mice, explaining the neural circuit cause. On molecular mechanism, we demonstrated an unprecedented discovery that Dcf1 triggers the dendritic spine and synaptic function through the recruitment of Lcn2 and activation of PSD95-NMDAR signaling. Removing this brake leads to memory damage. Our results highlight an unexpected regulatory mechanism of dendritic spine development and formation.

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Acknowledgments

This work was funded by the National Science Foundation of China (31070954, 81271253, 81471162), the Science and Technology Commission of Shanghai (14JC1402400), and the Key Innovation Project of Shanghai Municipal Education Commission (Grant No.14ZZ090).

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Authors and Affiliations

  1. Laboratory of molecular neural biology, School of life sciences, Shanghai University, 333 Nanchen Road, Shanghai, 200444, China

    Qiang Liu, Ruili Feng, Yu Chen, Guanghong Luo, Huang Yan, Rongfei Lin & Tieqiao Wen

  2. Department of Anatomy and Neurobiology, Tongji University School of Medicine, 1239 SiPing Road, Shanghai, 200092, China

    Ling Chen & Yuqiang Ding

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  1. Qiang Liu
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Correspondence to Tieqiao Wen.

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Electronic supplementary material

Supplementary Figure 1

The generation of Dcf1 knockout mice. a Verification of F2 deletion at the genomic level. A 700-bp band and lack of a 400-bp band indicate removal of F2 from the genomic DNA. b RT-PCR analysis of Dcf1 expression. The absence of the Dcf1 fragment confirmed gene knockout. c Thy1-EGFP mice were identified by PCR with a transgene (TR) that has a 415-bp band and an internal positive control (IP) that has a 324-bp band. (GIF 19 kb.)

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Supplementary Figure 2

Dcf1−/− mice exhibit abnormal spine synapse ultrastructure in area CA3. a Electron micrographs of synapses in WT and Dcf1−/− mice. b Dcf1−/− mice have significantly decreased spine head area. c Frequency histograms of spine head area for WT and Dcf1−/− neurons in area CA3. *P < 0.05, **P < 0.01, one way ANOVA; all data are presented as mean ± SEM; 4 mice per group. (GIF 105 kb.)

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Supplementary Figure 3

Dcf1 knockout causes the loss of dendritic spines in layer V/VI at different ages. a Neuronal development at P21, P42, and P90 in layer II/III. Neurons labeled with EGFP appeared at P90 but not at P21 and P42 in this layer. Scale bar: 100 μm. b The density of dendritic spines in layer V/VI of Dcf1−/− mice is decreased in comparison with that of WT mice at P21, P42, and P90. Scale bar: 5 μm. c Statistical comparison of dendritic spine density in layer V/VI of WT and Dcf1−/− mice demonstrates significant differences at P42 and P90. Analysis of dendritic spine density also showed a significant increase in WT mice from P21 to P42 and P90, whereas there was no increase in Dcf1−/− mice across ages. *P < 0.05, **P < 0.01, ***P < 0.001, two way ANOVA; all data are presented as mean ± SEM; 4 or 5 mice per group. (GIF 171 kb.)

High Resolution (TIFF 1.69 mb.)

Supplementary Figure 4

Dcf1 knockout reduces performance in memory tasks. a In the training trial of the spatial object relocation test, WT and Dcf1−/− mice spent equal time exploring the objects. b In the Morris water maze test, Dcf1−/− mice took significantly longer to locate the hidden platform only in the second trial on the first spatial training day. c-e Swimming path when searching for the hidden platform was much less directed in Dcf1−/− mice c, and the distance they swam on trial 3 d and trial 4 e of the reversal learning task was much longer compared with WT mice. Two tailed t-test, # P < 0.1, *P < 0.05,**P < 0.01,***P < 0.001; all data presented as mean ± SEM. 7–10 mice per group. (GIF 70 kb.)

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Supplementary Figure 5

Knocking down the level of Lcn2 in DG area of the hippocampus of KO mice can rescue the learning and memory of KO mice. a The lentivirus of pLKD-Ubc-EGFP-U6-shRNA Lcn2 can reduce the level of Lcn2 contrast the control in the neuro-2A cells. b Pictures showed that the lentivirus was expressed in the DG area of the hippocampus. Two tailed t-test. c Dcf1−/− mice injected with control only took significantly longer to locate the hidden platform contrast WT mice injected with control and KO mice injected with shRNA Lcn2 lentivirus in the second trial on the first spatial training day. Scale bar: 20 μm. # P < 0.1, *P < 0.05,**P < 0.01,***P < 0.001; all data presented as mean ± SEM. 6–9 mice per group. (GIF 99 kb.)

High Resolution (TIFF 1.07 mb.)

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Liu, Q., Feng, R., Chen, Y. et al. Dcf1 Triggers Dendritic Spine Formation and Facilitates Memory Acquisition. Mol Neurobiol 55, 763–775 (2018). https://doi.org/10.1007/s12035-016-0349-6

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