PT  - JOURNAL ARTICLE
AU  - Norma N. Zamora
AU  - Veronica T. Cheli
AU  - Diara A. SantiagoGonzález
AU  - Rensheng Wan
AU  - Pablo M. Paez
TI  - Deletion of voltage-gated calcium channels in astrocytes during demyelination reduces brain inflammation and promotes myelin regeneration in mice
AID  - 10.1523/JNEUROSCI.1644-19.2020
DP  - 2020 Mar 13
TA  - The Journal of Neuroscience
PG  - JN-RM-1644-19
4099  - http://www.jneurosci.org/content/early/2020/03/10/JNEUROSCI.1644-19.2020.short
4100  - http://www.jneurosci.org/content/early/2020/03/10/JNEUROSCI.1644-19.2020.full
AB  - To determine whether Cav1.2 voltage-gated Ca++ channels contribute to astrocyte activation, we generated an inducible conditional knockout mouse in which the Cav1.2 alpha subunit was deleted in GFAP positive astrocytes. This astrocytic Cav1.2 knockout mouse was tested in the cuprizone model of myelin injury and repair which causes astrocyte and microglia activation in the absence of a lymphocytic response. Deletion of Cav1.2 channels in GFAP positive astrocytes during cuprizone-induced demyelination leads to a significant reduction in the degree of astrocyte and microglia activation and proliferation in mice of either sex. Concomitantly, the production of pro-inflammatory factors such as TNFα, IL1β and TGFβ1 was significantly decreased in the corpus callosum and cortex of Cav1.2 knockout mice through demyelination. Furthermore, this mild inflammatory environment promotes oligodendrocyte progenitor cells maturation and myelin regeneration across the remyelination phase of the cuprizone model. Similar results were found in animals treated with nimodipine, a Cav1.2 Ca++ channel inhibitor with high affinity to the CNS. Mice of either sex injected with nimodipine during the demyelination stage of the CPZ treatment displayed a reduced number of reactive astrocytes and showed a faster and more efficient brain remyelination. Together, these results indicate that Cav1.2 Ca++ channels play a crucial role in the induction and proliferation of reactive astrocytes during demyelination; and attenuation of astrocytic voltage-gated Ca++ influx may be an effective therapy to reduce brain inflammation and promote myelin recovery in demyelinating diseases.SIGNIFICANCE STATEMENT: Reducing voltage-gated Ca++ influx in astrocytes during brain demyelination significantly attenuates brain inflammation and astrocyte reactivity. Furthermore, these changes promote myelin restoration and oligodendrocyte maturation throughout remyelination.