Research paperCRMP2 improves memory deficits by enhancing the maturation of neuronal dendritic spines after traumatic brain injury
Introduction
Traumatic brain injury (TBI) is a worldwide public health and socioeconomic problem as well as a major cause of death in adults. Approximately 5.3 million and 7.7 million individuals in the United States and Europe suffer from TBI-related sequelae (Langlois and Sattin, 2005; Tagliaferri et al., 2006). Learning and memory dysfunction are common complications after TBI (Azouvi et al., 2009; Hoskison et al., 2009).
Two-photon microscopy has revealed that the stability and plasticity of dendritic spines are closely related to learning and memory (Grutzendler et al., 2002). After TBI, spared neurons present significant morphological and functional changes, including a bead-like appearance of dendritic spines and a decrease in dendritic spine number, especially the number of mushroom-type dendritic spines (Winston et al., 2013; Winston et al., 2016). Dendritic spines are key to synapse formation (Frotscher et al., 2014; Kasai et al., 2010). Therefore, the decrease in spine number after TBI results in a decrease in synapse number and plasticity, thereby affecting learning and memory functions after TBI (Gao et al., 2011).
Collapsin response mediator protein-2 (CRMP2) is a microtubule-associated protein (Arimura et al., 2005; Gu et al., 2010; Hensley et al., 2010; Kawano et al., 2005) also known as Ulip2, CRMP-62, TOAD-64, DRP2 or DPYSL2 expressed in dendritic spines (Makihara et al., 2016). In central nerve system, it has been found to be related with axonal growth, neurotransmitter release and synaptic physiology (Chi et al., 2009; Hou et al., 2009). Deletion of CRMP2 leads to decrease of spine density in cortical neurons and aberrant behaviors which are symptoms of neuropsychiatric disorders (Makihara et al., 2016; Nakamura et al., 2016). Brain-specific deletion of CRMP2 leads to impaired learning and memory (Zhang et al., 2016). Besides, it is proved to have neuroprotective effect (Hensley et al., 2011; Nagai et al., 2016). At present, changes in the morphology of dendritic spines are believed to be caused by cytoskeleton remodeling (Bellot et al., 2014; Brody et al., 2015; Lei et al., 2016). Although the morphology of dendritic spines is closely related to learning and memory function (Gipson and Olive, 2017; Segal, 2017), no research thus far has focused on the potential relationship between CRMP2 and the morphological changes of dendritic spines after TBI. Moreover, whether CRMP2 can improve learning and memory after TBI is still unknown. Therefore, we studied the effect of CRMP2 on dendritic spine morphology and learning and memory function after TBI.
Section snippets
Animals
All procedures were approved by the Institutional Animal Care and Use Committee of Shanghai Jiao Tong University School of Medicine and carried out in accordance with the guidelines of the National Institutes of Health regarding animal care. Thy1-GFP mice were donated by professor Xu Nan-Jie, researcher at the Shanghai Jiao Tong University School of Medicine. ICR male mice and E18 mice were purchased from Shanghai Slac Experimental Animal Center.
Plasmid and AAV
The Institutional Biosafety Committee of the
Morphological changes of dendritic spines after TBI
We performed CCI on Thy1-GFP mice (Fig. 1A). Through immunofluorescence experiments, we found that dendrites of neurons swelled, fractured and formed a bead-like structure (Fig. 1B) in the cortex and hippocampus 1 day after injury. Dendritic spine density was significantly reduced in the injured side, from 13.91 ± 0.21 to 7.9 ± 0.05 per 10um. Meanwhile, the loss of thin-type dendritic spines was dominant, accounting for 17.98% ± 0.25 at 1 day post injury. At 7 days after TBI, the neurons in the
Discussion
In vivo studies have found that animals present impaired brain functions to some degree after TBI (Azouvi et al., 2009; Hart and Sander, 2017), accompanied by a decrease in CRMP2 expression (Campbell et al., 2012; Zhang et al., 2007). Thus, whether rescuing CRMP2 expression could restore brain function appeared to be a particularly meaningful question. Interestingly, Dr. Khanna's team fused a CRMP2 peptide (CBD3) to the HIV-Tat protein to generate an agent that can prevent neural death after
Author contribution
Dong-Fu Feng designed research; Yi-Yu sun and Liang Zhu performed research and wrote the paper; Zhao-Liang sun performed data analysis.
Acknowledgments
This work was supported by National Natural Science Foundation of China (81372047, 81772059).
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Yi-Yu Sun and Liang Zhu contributed equally to this article.