Project

Noradrenergic modulation of seizures and epilepsy: the good, the bad and the ugly

Duration
01 November 2021 → Ongoing
Funding
Research Foundation - Flanders (FWO)
Research disciplines
  • Medical and health sciences
    • Neurophysiology
    • Neurological and neuromuscular diseases
    • Neurosciences not elsewhere classified
Keywords
Epilepsy noradrenaline optoand chemogenetics
 
Project description

The locus coeruleus (LC) is a noradrenergic brainstem nucleus and the sole source of noradrenaline (NA) in the neocortex, hippocampus and cerebellum. NA exerts complex concentration dependent neuromodulatory effects, binding to a variety of different adrenoceptor subtypes with varying affinity. In this project we will investigate three hypothesized roles for the LC-NA system in seizures and epilepsy: 1) a ‘good’ role, where NA at low and moderate concentrations, as suggested by literature, may act as a seizure suppressing agent, 2) a ‘bad’ role, where NA at high concentrations may facilitate seizures and 3) an ‘ugly’ role, where NA released in relation to seizures in great quantities, boosts synaptic plasticity and facilitates the formation of seizure networks, thus leading the transformation from a healthy to an epileptic brain. Addressing these hypotheses is enabled by the availability and recent validation of state-of-the-art opto- and chemogenetic tools which allow both acute time-specific and chronic excitation or inhibition of the LC-NA system in both acute seizure models and chronic epilepsy models. The disease mechanisms explored in this project are novel and hold potential to greatly improve our understanding of epilepsy and seizure disorders and open new avenues for treatments for an indication where one third of patients remain medication resistant.