Toro-Fernández Luisa Fernanda, Zuluaga-Monares Juan Camilo, Saldarriaga-Cartagena Ana María, Cardona-Gómez Gloria Patricia, Posada-Duque Rafael
Instituto de Biología, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Medellín, Colombia.
Área de Neurobiología Celular y Molecular, Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia.
Front Cell Neurosci. 2021 Nov 1;15:643717. doi: 10.3389/fncel.2021.643717. eCollection 2021.
Glutamate excitotoxicity triggers overactivation of CDK5 and increases calcium influx in neural cells, which promotes dendritic retraction, spine loss, increased mitochondrial calcium from the endoplasmic reticulum, and neuronal death. Our previous studies showed that CDK5 knockdown (KD) in astrocytes improves neurovascular integrity and cognitive functions and exerts neuroprotective effects. However, how CDK5-targeted astrocytes affect calcium regulation and whether this phenomenon is associated with changes in neuronal plasticity have not yet been analyzed. In this study, CDK5 KD astrocytes transplanted in CA3 remained at the injection site without proliferation, regulated calcium in the CA1 hippocampal region after excitotoxicity by glutamate in hippocampal slices, improving synapsin and PSD95 clustering. These CDK5 KD astrocytes induced astrocyte stellation and neuroprotection after excitotoxicity induced by glutamate Also, these effects were supported by CDK5 inhibition (CDK5i) through intracellular stabilization of calcium levels in astrocytes. Additionally, these cells in cocultures restored calcium homeostasis in neurons, redistributing calcium from somas to dendrites, accompanied by dendrite branching, higher dendritic spines and synapsin-PSD95 clustering. In summary, induction of calcium homeostasis at the CA1 hippocampal area by CDK5 KD astrocytes transplanted in the CA3 area highlights the role of astrocytes as a cell therapy target due to CDK5-KD astrocyte-mediated synaptic clustering, calcium spreading regulation between both areas, and recovery of the intracellular astrocyte-neuron calcium imbalance and plasticity impairment generated by glutamate excitotoxicity.
谷氨酸兴奋性毒性会触发CDK5的过度激活，并增加神经细胞中的钙内流，这会促进树突回缩、棘突丧失、内质网中流入线粒体的钙增加以及神经元死亡。我们之前的研究表明，星形胶质细胞中CDK5基因敲低（KD）可改善神经血管完整性和认知功能，并发挥神经保护作用。然而，靶向CDK5的星形胶质细胞如何影响钙调节以及这种现象是否与神经元可塑性的变化相关，尚未得到分析。在本研究中，移植到CA3区的CDK5基因敲低星形胶质细胞停留在注射部位，没有增殖，在海马切片中谷氨酸诱导的兴奋性毒性后，调节CA1海马区的钙，改善突触素和PSD95的聚集。这些CDK5基因敲低星形胶质细胞在谷氨酸诱导的兴奋性毒性后诱导星形胶质细胞形成星状并发挥神经保护作用。此外，这些作用得到了CDK5抑制（CDK5i）的支持，通过细胞内稳定星形胶质细胞中的钙水平来实现。此外，共培养中的这些细胞恢复了神经元中的钙稳态，将钙从胞体重新分布到树突，伴随着树突分支增加、更高的树突棘以及突触素-PSD95聚集。总之，移植到CA3区的CDK5基因敲低星形胶质细胞在CA1海马区诱导钙稳态，突出了星形胶质细胞作为细胞治疗靶点的作用，这是由于CDK5基因敲低星形胶质细胞介导的突触聚集、两个区域之间钙扩散的调节以及谷氨酸兴奋性毒性产生的细胞内星形胶质细胞-神经元钙失衡和可塑性损伤的恢复。
