NeuroPSI – Paris-Saclay University

Astrocytes control of extracellular homeostasis under physiological and pathological conditions

Abstract
In the first part of my PhD, I studied cerebral ischemia, a condition characterized by the interruption of blood supply to the brain. I studied the effects of hypothermia, an effective yet poorly understood clinical approach, against ischemia in the cerebellum, a structure particularly vulnerable to this pathology. Using electrophysiology and ex vivo imaging methods, I here show that lowering temperature grants a delay in the occurrence of cerebellar edema and extracellular K+ accumulation during ischemia. Similarly, Bergmann glia (BG), a type of radial astrocyte in the cerebellum, responds with morphological changes as well as membrane depolarization, that are postponed in hypothermic conditions. My results therefore show that, during a cerebellar ischemic episode, hypothermia reduces the deleterious homeostatic changes regulated by BG.
In the second part of my PhD, I studied the role of astrocytes in dopaminergic modulations of the prefrontal cortex (PFC). I first studied their indirect contribution by elucidating, through electrophysiological and pharmacological approaches, the intracellular pathway underlying the involvement of D-serine, a co-agonist of NMDA receptors and well-known gliotransmitter, in dopamine-mediated regulation of neurotransmission. I then studied the direct contribution of astrocytes to the regulation of extracellular dopamine levels in the prefrontal cortex (PFC). We indeed hypothesized that prefrontal dopamine is redistributed via astroglial release, since a recent study showed that the astroglial expression of the vesicular dopamine transporter VMAT2 contributes to the dopaminergic homeostasis of the PFC. Using ex vivo imaging approaches with a fluorescent dopaminergic sensor in PFC slices, I show that spontaneous dopamine releases are enhanced by chemogenetic and pharmacological activation of astrocytes. I then studied the impact of this astroglial modulation on synaptic transmission and excitability of PFC pyramidal neurons. Using different electrophysiological approaches, I observed that intracellular diffusion of dopamine in the astrocytic network upregulates synaptic transmission at the postsynaptic level and that these regulations are absent in mouse lines lacking astrocytic gap junctions and VMAT2. Finally, my results indicate that neuronal excitability is little affected by astrocytic dopamine. Taken together these results are consistent with the hypothesis of an astrocytic dopamine release modulating neuronal activities of the PFC. These processes remain to be further investigated but seem to involve interconnection of the astroglial network as well as the vesicular transporter VMAT2.
Taken together, this body of work shows the essential role of astrocytes in the maintenance of extracellular homeostasis and highlight their importance in physio-pathological processes.

Jury Members

• • Sylvie GRANON, President (NeuroPSI, Saclay)
  • Nathalie ROUACH (Reviewer, Collège de France)
  • Thomas FRERET (Reviewer, Université de Caen Normandie)
  • Mariano CASADO (Jury member, ENS, Paris)
  • Carole ESCARTIN (Jury member, CEA, MIRCEN)
  • Delphine BUREL (Invited, Université de Rouen Normandie)

and

• Micaela GALANTE & Glenn DALLERAC (Institut NeuroPSI, Saclay)