Targeting CDK5 in Astrocytes Promotes Calcium Homeostasis Under Excitotoxic Conditions
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 astrocyt...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-11-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2021.643717/full |
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| author | Luisa Fernanda Toro-Fernández Luisa Fernanda Toro-Fernández Juan Camilo Zuluaga-Monares Juan Camilo Zuluaga-Monares Ana María Saldarriaga-Cartagena Ana María Saldarriaga-Cartagena Gloria Patricia Cardona-Gómez Rafael Posada-Duque Rafael Posada-Duque |
| author_facet | Luisa Fernanda Toro-Fernández Luisa Fernanda Toro-Fernández Juan Camilo Zuluaga-Monares Juan Camilo Zuluaga-Monares Ana María Saldarriaga-Cartagena Ana María Saldarriaga-Cartagena Gloria Patricia Cardona-Gómez Rafael Posada-Duque Rafael Posada-Duque |
| author_sort | Luisa Fernanda Toro-Fernández |
| collection | DOAJ |
| description | 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 ex vivo hippocampal slices, improving synapsin and PSD95 clustering. These CDK5 KD astrocytes induced astrocyte stellation and neuroprotection after excitotoxicity induced by glutamate in vitro. Also, these effects were supported by CDK5 inhibition (CDK5i) in vitro 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. |
| first_indexed | 2024-12-20T04:04:56Z |
| format | Article |
| id | doaj.art-7db00dc2ce5c4d10b9073b9e0606079b |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-20T04:04:56Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-7db00dc2ce5c4d10b9073b9e0606079b2022-12-21T19:54:04ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022021-11-011510.3389/fncel.2021.643717643717Targeting CDK5 in Astrocytes Promotes Calcium Homeostasis Under Excitotoxic ConditionsLuisa Fernanda Toro-Fernández0Luisa Fernanda Toro-Fernández1Juan Camilo Zuluaga-Monares2Juan Camilo Zuluaga-Monares3Ana María Saldarriaga-Cartagena4Ana María Saldarriaga-Cartagena5Gloria Patricia Cardona-Gómez6Rafael Posada-Duque7Rafael Posada-Duque8Instituto de Biología, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Medellín, ColombiaÁrea de Neurobiología Celular y Molecular, Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, ColombiaInstituto de Biología, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Medellín, ColombiaÁrea de Neurobiología Celular y Molecular, Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, ColombiaInstituto de Biología, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Medellín, ColombiaÁrea de Neurobiología Celular y Molecular, Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, ColombiaÁrea de Neurobiología Celular y Molecular, Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, ColombiaInstituto de Biología, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Medellín, ColombiaÁrea de Neurobiología Celular y Molecular, Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, ColombiaGlutamate 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 ex vivo hippocampal slices, improving synapsin and PSD95 clustering. These CDK5 KD astrocytes induced astrocyte stellation and neuroprotection after excitotoxicity induced by glutamate in vitro. Also, these effects were supported by CDK5 inhibition (CDK5i) in vitro 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.https://www.frontiersin.org/articles/10.3389/fncel.2021.643717/fullastrocytecalcium homeostasisCDK5excitotoxicitysynaptic proteinhippocampus |
| spellingShingle | Luisa Fernanda Toro-Fernández Luisa Fernanda Toro-Fernández Juan Camilo Zuluaga-Monares Juan Camilo Zuluaga-Monares Ana María Saldarriaga-Cartagena Ana María Saldarriaga-Cartagena Gloria Patricia Cardona-Gómez Rafael Posada-Duque Rafael Posada-Duque Targeting CDK5 in Astrocytes Promotes Calcium Homeostasis Under Excitotoxic Conditions Frontiers in Cellular Neuroscience astrocyte calcium homeostasis CDK5 excitotoxicity synaptic protein hippocampus |
| title | Targeting CDK5 in Astrocytes Promotes Calcium Homeostasis Under Excitotoxic Conditions |
| title_full | Targeting CDK5 in Astrocytes Promotes Calcium Homeostasis Under Excitotoxic Conditions |
| title_fullStr | Targeting CDK5 in Astrocytes Promotes Calcium Homeostasis Under Excitotoxic Conditions |
| title_full_unstemmed | Targeting CDK5 in Astrocytes Promotes Calcium Homeostasis Under Excitotoxic Conditions |
| title_short | Targeting CDK5 in Astrocytes Promotes Calcium Homeostasis Under Excitotoxic Conditions |
| title_sort | targeting cdk5 in astrocytes promotes calcium homeostasis under excitotoxic conditions |
| topic | astrocyte calcium homeostasis CDK5 excitotoxicity synaptic protein hippocampus |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2021.643717/full |
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