Applications of optogenetic and chemogenetic methods to seizure circuits: Where to go next?
Both optogenetic and chemogenetic methodologies share the common feature of enabling cell‐type and pathway‐specific activation or silencing of neurons, and have been reviewed in detail elsewhere (Bernstein & Boyden, 2011; Sjulson, Cassataro, DasGupta, & Miesenböck, 2016; Urban & Roth, 2015). Briefly, optogenetics accomplishes this modulation through the expression of light‐sensitive ion channels or pumps; when these actuators are expressed in cells of interest, focal light delivery results in neuronal excitation (e.g., channelrhodopsin 2, ChR2) or inhibition (e.g., archaerhodopsin, ArchT, halorhodopsin, NpHR). The chemogenetic approach makes use of genetically modified G protein–coupled receptors. These receptors, commonly referred to as “designer receptors exclusively activated by designer drugs” or DREADDs, include the first‐generation DREADDs (hM4Di, hM3Dq, Gs‐D), which evolved from the human muscarinic receptor and the more recently developed “Kappa opioid receptor DREADDs” (KORD), which evolved from the kappa opioid receptor. These DREADDs no longer respond to their endogenous ligand but, instead, display high affinity for other putatively inert compounds (e.g., clozapine‐n‐oxide [CNO], Salvinorin B [SalB]; but see below). Thus, with the DREADD approach, focal or systemic delivery of the DREADD ligand results in neuronal silencing or excitation.
Here, I discuss (1) the comparative strengths of optogenetic and chemogenetic approaches in epilepsy, (2) the importance of microcircuit–macrocircuit interactions in seizure mapping, (3) ways in which optogenetics have allowed tests of causality within specific seizure pathways, and (4) applications of optogenetic and chemogenetic approaches in behavioral neuroscience that may be applied to epilepsy. This review is not intended to serve as a comprehensive overview of all the studies in epilepsy employing these methods, as several recent reviews have done this quite well (Choy, Duffy, & Lee, 2017; Krook‐Magnuson & Soltesz, 2015; Tønnesen & Kokaia, 2017; Tung, Berglund, & Gross, 2016), but rather intends to use select examples at the level of whole‐animal or macrocircuit manipulations to highlight the potential of these methods to answer questions that were previously unapproachable.