Thesis defense Martin Perescis (Donders series 526)

10 February 2022

Promotor: Prof. Dr. Gilles van Luijtelaar
Co-promotor: Dr. Tineke van Rijn

Early pharmacological manipulations and seizure susceptibility later in life.

Genetically identical animals often display a great deal of individual variation in the expression of traits. This is also the case for various types of seizures. The aim of this thesis is to shed light on the contribution of the endogenous environment and early manipulation thereof to the development of seizures, with an emphasis on absence seizures. The focus is on the endogenous neurotransmitters GABA and the endogenous cannabinoid system because these two interconnected systems are of vital importance for the expression of epileptic phenomena. We hypothesize that the endogenous tone of these neurotransmitters during early development is of great importance for the expression of absence epilepsy later in life. Moreover, it is expected that there is an influence on related traits, i.e. comorbidities such as depression, as well. By means of several EEG experiments in rats, it is shown that the GABA-ergic system in the cortico-thalamo-cortical system is a key factor in explaining the contribution of the endogenous environment to variation in absence seizures and behavior. The role of the endocannabinoid system is less clear. Activation of the endocannabinoid system results in acute effects on absence seizures and behavior, but we did not find any evidence that early manipulation of the endocannabinoid system results in any lasting changes, in contrast to what is often reported and in contrast to early GABA-ergic manipulation. Moreover, we found that a blockage of the endocannabinoid system with antagonists leads to a high risk of severe convulsive seizures. This is one of several safety issues that has led to the discontinuation of the development of such drugs. In conclusion, the experiments described in this thesis have shown that various types of manipulation of the GABA-ergic endogenous environment result in changes in brain development, which are expressed in long lasting or even permanent alterations in seizures and comorbidities.