Astrocytic Ca2+ activation by chemogenetics mitigates the effect of kainic acid‐induced excitotoxicity on the hippocampus

Author:

Hernández‐Martín Nira12ORCID,Martínez María Gómez1,Bascuñana Pablo12,Fernández de la Rosa Rubén13,García‐García Luis124,Gómez Francisca124,Solas Maite5,Martín Eduardo D.6,Pozo Miguel A.127

Affiliation:

1. Instituto Pluridisciplinar Universidad Complutense de Madrid Madrid Spain

2. Instituto de Investigación Sanitaria San Carlos (IdISSC) Hospital Clínico San Carlos Madrid Spain

3. Bioimac Universidad Complutense de Madrid Madrid Spain

4. Departamento de Farmacología, Farmacognosia y Botánica, Facultad de Farmacia Universidad Complutense de Madrid Madrid Spain

5. Facultad de Farmacia Universidad de Navarra Pamplona Spain

6. Instituto Cajal, CSIC Madrid Spain

7. Facultad de Medicina Universidad Complutense de Madrid Madrid Spain

Abstract

AbstractAstrocytes play a multifaceted role regulating brain glucose metabolism, ion homeostasis, neurotransmitters clearance, and water dynamics being essential in supporting synaptic function. Under different pathological conditions such as brain stroke, epilepsy, and neurodegenerative disorders, excitotoxicity plays a crucial role, however, the contribution of astrocytic activity in protecting neurons from excitotoxicity‐induced damage is yet to be fully understood. In this work, we evaluated the effect of astrocytic activation by Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) on brain glucose metabolism in wild‐type (WT) mice, and we investigated the effects of sustained astrocyte activation following an insult induced by intrahippocampal (iHPC) kainic acid (KA) injection using 2‐deoxy‐2‐[18F]‐fluoro‐D‐glucose (18F‐FDG) positron emission tomography (PET) imaging, along with behavioral test, nuclear magnetic resonance (NMR) spectroscopy and histochemistry. Astrocytic Ca2+ activation increased the 18F‐FDG uptake, but this effect was not found when the study was performed in knock out mice for type‐2 inositol 1,4,5‐trisphosphate receptor (Ip3r2−/−) nor in floxed mice to abolish glucose transporter 1 (GLUT1) expression in hippocampal astrocytes (GLUT1ΔGFAP). Sustained astrocyte activation after KA injection reversed the brain glucose hypometabolism, restored hippocampal function, prevented neuronal death, and increased hippocampal GABA levels. The findings of our study indicate that astrocytic GLUT1 function is crucial for regulating brain glucose metabolism. Astrocytic Ca2+ activation has been shown to promote adaptive changes that significantly contribute to mitigating the effects of KA‐induced damage. This evidence suggests a protective role of activated astrocytes against KA‐induced excitotoxicity.

Funder

Agencia Estatal de Investigación

Ministerio de Ciencia, Innovación y Universidades

Instituto de Salud Carlos III

Universidad Complutense de Madrid

Comunidad de Madrid

Publisher

Wiley

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