Astrocytes fine-tune neural information processing and behavior by actively modulating synaptic function through the release of gliotransmitters such as glutamate, ATP or D-serine. In the primary somatosensory cortex, in particular, endocannabinoids acting through astrocyte CB₁ receptors (CB₁Rs) induce cytosolic Ca²⁺ elevations, ATP/adenosine release and activation of presynaptic adenosine A₁Rs leading to synaptic depression.

Multiple sclerosis (MS) is a chronic, inflammatory and demyelinating disease that leads to motor, sensory and cognitive deficits associated to cortical synaptic dysfunction. Astrocytes acquire important disease-promoting functions that include toxicity to oligodendrocytes and neurons. However, studies specifically addressing the changes in astrocyte-to-neuron communication in MS are lacking.

Here we addressed changes in CB₁R-mediated cortical astrocyte-to-neuron communication in the experimental autoimmune encephalomyelitis (EAE) model of MS. Endocannabinoids released upon depolarization of cortical neurons predominantly potentiated synaptic transmission during EAE suggesting that CB₁Rs preferentially engage the release of glutamate rather than ATP/adenosine from astrocytes. In addition, spike timing-dependent plasticity mediated by endocannabinoid-to-astrocyte signaling shifted from depression (t-LTD) to potentiation (t-LTP) in EAE mice. Cortical astrocytes displayed a 2-fold increase in spontaneous Ca²⁺ activity ex vivo that correlated with increased basal slow inward currents (SICs) originated by astrocytic glutamate release. However, we measured attenuated Ca²⁺ responses mediated by pharmacological activation of CB₁Rs and metabotropic glutamate 2/3 receptors, as well as reduced G_q– and G_i-mediated astrocyte Ca²⁺ signaling as determined using DREADDs, in EAE astrocytes ex vivo. Consistent with these observations, in vivo analysis of astrocyte Ca²⁺ dynamics in freely behaving mice unveiled spontaneous astrocyte Ca²⁺ transients of increased duration and attenuated responses to the cannabinoid agonist D⁹-THC during EAE. Acute incubation of cortical slices with TNFα, IL1α and C1q deregulated spontaneous and agonist-evoked astrocyte Ca²⁺ activity thus suggesting that alterations in EAE mice may result from an increased inflammatory environment. Consistently, we measured increased astrocyte reactivity, microglial activation and expression of inflammatory molecules in the somatosensory cortex during EAE. Collectively, these results suggest that aberrant astrocyte Ca²⁺ dynamics leading to deregulated gliotransmitter release may contribute to excitatory-inhibitory imbalance in MS.