Applications of optogenetic and chemogenetic methods to seizure circuits: Where to go next?

Abstract

Epilepsy is the quintessential circuit disorder, with seizure activity propagating through anatomically constrained pathways. These pathways, necessary for normal sensory, motor, and cognitive function are hijacked during seizures. Understanding the network architecture at the level of both local microcircuits and distributed macrocircuits may provide new therapeutic avenues for the treatment of epilepsy. Over the past decade, optogenetic and chemogenetic tools have enabled previously impossible levels of functional circuit mapping in neuroscience. In this review, examples of the application of optogenetics and chemogenetics to epilepsy are raised, the comparative strengths and weaknesses of these approaches are discussed for both preclinical and translational applications, and recent applications of these approaches in other areas of neuroscience are highlighted. These points are raised in an effort to highlight the potential of these methods to address additional unanswered questions in epilepsy.

An Excitatory Circuit in the Perioculomotor Midbrain for Non-REM Sleep Control

“…Optogenetic stimulation of axon terminals could, in principle, evoke antidromic spiking and activation of other collateral projections. We thus tested the effect of local chemogenetic activation, which causes slow depolarization of axon terminals through G protein-coupled signaling and is unlikely to induce antidromic spiking (Forcelli, 2017). In Calca Cre mice injected with AAV-DIO-hM3D(Gq)-mCherry in the pIII region, local CNO injection in the POA caused a significant increase in NREM sleep ( Figure S7E), further demonstrating a contribution of the POA projection to sleep regulation.…”

Proceedings of the Epilepsy Foundation's 2017 Cannabinoids in Epilepsy Therapy Workshop

“…Several cutting-edge technologies are being developed to refine and enhance the real-time visualization of neuronal network dynamics providing a unique opportunity for their application in preclinical seizure models. First, the development of optogenetic and chemogenetic techniques have provided enhanced temporal and spatial control over specific neuronal populations, allowing for functional circuit mapping [35]. Individually, both techniques offer potential for future clinical treatment strategies similar to what was achieved for deep brain stimulation approaches [36, 37].…”

Specificity, Versatility, and Continual Development: The Power of Optogenetics for Epilepsy Research

“…It is estimated that one third or more of epilepsy patients do not achieve adequate seizure control with current treatment options, and current treatment options can have major negative side effects (de Tisi et al, 2011 ; Perucca and Gilliam, 2012 ; Duchowny and Bhatia, 2014 ; Laxer et al, 2014 ). Optogenetics, by providing researchers with a powerful and flexible tool, is allowing significant advances in our understanding of epilepsy (for additional reviews related to the general topic of epilepsy and optogenetics, see also Krook-Magnuson et al, 2014a ; Krook-Magnuson and Soltesz, 2015 ; Tung et al, 2016 ; Choy et al, 2017 ; Forcelli, 2017 ; Tønnesen and Kokaia, 2017 ). Here, we discuss this work in epilepsy research highlighting how well-suited an optogenetic approach is to epilepsy research in particular and how the benefits of an optogenetic approach can be leveraged in future research.…”