Illuminating seizures: optogenetic approaches to studying networks in epilepsy

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The ability to selectively and precisely manipulate elements of neuronal circuitry provides researchers with a valuable tool to study physiological processes and neurological disorders (Boyden, 2015; Deisseroth, 2015). One area of research benefiting from tools that allow selective manipulation is epilepsy research (Krook‐Magnuson & Soltesz, 2015). Epilepsy is a heterogeneous collection of neurological disorders characterized by recurrent spontaneous seizures. Approximately 65 million people have epilepsy (England, Liverman, Schultz, & Strawbridge, 2012). Unfortunately, a basic understanding of what causes the initiation of spontaneous seizures, how seizures spread or propagate through networks (and why they only sometimes propagate), and what ultimately controls the termination of seizures remains largely unknown. This lack of understanding of fundamental aspects of epilepsy hampers the development of needed new treatment options. New treatment options are absolutely needed; a third or more of patients with epilepsy suffer from uncontrolled seizures (Laxer et al., 2014).
Optogenetics, which rests on genetically encoded light‐sensitive proteins called opsins, allows for a high degree of selectivity and flexibility in regard to the circuit elements being manipulated, the timing of that manipulation, and the type of modulation. Optogenetics can also be combined with other techniques, including functional magnetic resonance imaging (Weitz et al., 2015; Kim, Adhikari, & Deisseroth, 2017). This specificity and flexibility allows epilepsy researchers to use optogenetics to induce seizures to study seizure dynamics and propagation tendencies, as well as to inhibit seizures, through selectively manipulating circuit elements, often selectively at the time of seizures. Optogenetics has also been used, for example, to study changes in epileptic tissue. In this In Focus section of the Journal of Neuroscience Research, Choy and colleagues provide a review of some of the ways in which optogenetics has been harnessed in the field of epilepsy research to provide new insights into seizures and epilepsy (Choy, Duffy, & Lee, 2017). Indeed, Table 1 in their review highlights over 30 different in vivo optogenetic approaches taken to inhibit seizures in various animal models of epilepsy, and studies using optogenetics to induce seizures or in combination with other methods have provided additional insights. The specificity achievable with optogenetics, and its flexible platform, ensure that the number of studies using optogenetics in epilepsy research will continue to grow.
The insights gained through studies using optogenetics for selective manipulation provide new information about seizure networks, new hypotheses to be tested, and, importantly, new avenues for treatment options. For example, previously we demonstrated that on‐demand optogenetic excitation of parvalbumin interneurons contralateral to the presumed seizure focus was able to inhibit spontaneous seizures in a mouse model of temporal lobe epilepsy (Krook‐Magnuson, Armstrong, Oijala, & Soltesz, 2013). Together with other findings, these results raised the possibility that this seizure inhibition was mediated by parvalbumin neurons providing direct commissural inhibition to the contralateral hippocampus. In an original research article in this In Focus section of the Journal of Neuroscience Research, my lab presents our findings that parvalbumin‐positive hippocampal neurons provide a relatively sparse innervation of the contralateral hippocampal formation in control animals (Christenson Wick, Leintz, Xamonthiene, Huang, & Krook‐Magnuson, 2017). However, by 6 months after the initial epileptogenic insult, this commissural inhibitory connection is significantly expanded and preferentially targets the dentate gyrus. These findings illustrate the impact that optogenetic techniques can indirectly have on the field of epilepsy research. Until optogenetic techniques are used directly in a clinical setting, optogenetics will also have an indirect, rather than direct, effect on epilepsy care by providing new insight into the disorder and guiding new intervention strategies.
Optogenetics is not the only means for selective manipulation of circuit elements.

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