Deletion of Voltage-Gated Calcium Channels in Astrocytes during Demyelination Reduces Brain Inflammation and Promotes Myelin Regeneration in Mice

Abstract

To determine whether Cav1.2 voltage-gated Ca 21 channels contribute to astrocyte activation, we generated an inducible conditional knockout mouse in which the Cav1.2 a 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 cuprizoneinduced 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 proinflammatory factors such as TNFa, IL1b and TGFb1 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 21 channel inhibitor with high affinity to the CNS. Mice of either sex injected with nimodipine during the demyelination stage of the cuprizone 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 21 channels play a crucial role in the induction and proliferation of reactive astrocytes during demyelination; and that attenuation of astrocytic voltage-gated Ca 21 influx may be an effective therapy to reduce brain inflammation and promote myelin recovery in demyelinating diseases.

Ion Channels as New Attractive Targets to Improve Re-Myelination Processes in the Brain

“…However, microglial cells do not express functional Cav1.2 channels [ 150 ], thus the anti-inflammatory effects of these drugs are likely mediated by their block on other cell types [ 72 ]. Recently, it was found that animals injected with nimodipine during CPZ-induced demyelination displayed a reduced astrocyte and microglia activation and proliferation as well as a faster and more efficient brain remyelination [ 74 ]. Cav1.2 channels are not present in mature OLs [ 96 , 104 ], but they are expressed by OPCs where they are essential for maturation [ 100 , 101 ], as mentioned above.…”

Design of an imaging probe to monitor real-time redistribution of L-type voltage gated calcium channels in astrocytic glutamate signalling

“…This chemical probe provides an alternative to current methods that rely on immunological techniques or molecular biology modifications to monitor protein localization. It also paves the way to investigate the role of LTCC dynamics in calcium events in neurological disorders, e.g., Alzheimer’s, Parkinson’s, and multiple sclerosis [36, 63–67].…”

EGB761 ameliorates chronic cerebral hypoperfusion-induced cognitive dysfunction and synaptic plasticity impairment

“…The diameter of axons and their fibre bundles were measured. The g-ratio (the diameter of fibre bundle of axon versus axon diameter) was calculated to evaluate the demyelination of axons [ 53 ].…”