טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentAssaf Fadi
SubjectOpto- and Chemogenetic Stimulation for Treating Experimental
Epileptic Seizures and Parkinson's Disease
DepartmentDepartment of Medicine
Supervisor Professor Yitzhak Schiller
Full Thesis textFull thesis text - English Version


Abstract

In recent  years new revolutionary genetically-based methods have been developed to modulate neuronal activity. These include optogenetics, in which light-sensitive ionic channels and pumps are used to excite or inhibit neurons by light, and chemogenetics, in which genetically modified G protein receptors are used to excite or inhibit neurons by synthetic otherwise inert small molecules.  In my research thesis, I utilized of optogenetic stimulation paradigms to eliminate experimental epileptic seizures, and used the chemogenetic agent designer receptors exclusively activated by designer drugs (DREADDs) to treat experimental Parkinson’s disease (PD).

In the case of epilepsy I have shown that 4-aminopyridine (4-AMP) induced neocortical epileptic can be eliminated both by prolonged open-loop DC-like activation of excitatory pyramidal neurons, as well as by responsive opto-stimulation of parvalbumin (PV) expressing interneurons during seizures (ictal state).  Surprisingly, optogenetic stimulation of inhibitory PV interneuron in between seizures (inter-ictal state) had powerful ictogenetic effects and generated seizures. 

In the case of experimental PD I have shown that motor performances can be significantly improved by modulating the activity of different basal ganglia nuclei and pathways using excitatory and inhibitory DREADDS. More specifically, in 6-hydroxy dopamine (6-OHDA) induced experimental PD motor velocity, rotations (open field test) and the ability to remain on a rotating rod (Rota-Rod test) were significantly improved by suppressing the indirect pathway or the output basal ganglia nuclei, and by activating the subthalamic nucleus.

Taken together the results of my thesis shown the therapeutic potential of opto- and chemogenetic neuromodulation paradigms for treating brain diseases.