Chemogenetic modulation of CX3CR1+ cells in a mouse model of drug-resistant limbic epilepsy.

Project Details

Description

Temporal lobe epilepsy is a common, yet drug-resistant form of
epilepsy with a high unmet medical need. Microglia, the brain
resident CX3CR1+ macrophages, are in close interaction with
neuronal cells, both via indirect (e.g. release of soluble mediators
such as inflammatory cytokines) and direct (e.g. synaptic pruning)
contacts. Both modes of gliocommunication seem able to alter the
excitatory/inhibitory balance of neuronal networks, thereby possibly
affecting excitability and seizure susceptibility. The use of G-proteincoupled Designer Receptors Exclusively Activated by Designer Drugs
(DREADDs) now enable cell-specific and selective interference with
microglial signalling. This opens interesting perspectives for
chemogenetic microglial modulation as an innovative strategy to
modulate epileptic seizures and epileptogenesis. I hypothesize that
Gi-DREADD-based microglial silencing will have short-term effects
upon brain excitability and seizure burden, as well as long-term
effects resulting in repopulation of microglia with a more antiinflammatory phenotype able to affect epilepsy disease progression.
Therefore, I will test the effects of Gi-DREADD-based modulation of
microglia/CX3CR1+ cells on the amount of spontaneous recurrent
seizures via EEG, microglial phenotypes, neuronal cell death and
astrocyte activation, in a mouse model for temporal lobe epilepsy
with established refractory seizures and during the process of
epileptogenesis, which is completely novel.
AcronymFWOTM1061
StatusActive
Effective start/end date1/11/2131/10/23

Flemish discipline codes

  • Neurological and neuromuscular diseases
  • Neurophysiology
  • Neurosciences not elsewhere classified
  • Pharmacology not elsewhere classified

Keywords

  • Temporal lobe epilepsy
  • Microglia/CX3CR1+ cells
  • Designer Receptors Exclusively Activated by Designer Drugs (DREADD)