Seizing Control of Neuronal Activity: Chemogenetic Applications in Epilepsy

Abstract

The fundamental commonality across pharmacotherapies for the epilepsies is the modulation of neuronal excitability. This poses a clear challenge—patterned neuronal excitation is essential to normal function, thus disrupting this activity leads to side effects. Moreover, the efficacy of current pharmacotherapy remains incomplete despite decades of drug development. Approaches that allow for the selective targeting of critical populations of cells and particular pathways in the brain have the potential to both avoid side effects and improve efficacy. Chemogenetic methods, which combine the selective expression of designer receptors with designer drugs, have rapidly grown in use in the neurosciences, including in epilepsy. This review will briefly highlight the history of chemogenetics, their applications to date in epilepsy, and the potential (and potential hurdles to overcome) for future translation.

Activation of GABAergic neurons in anterior cingulate cortex and their impacts on pulpitis-induced pain

“…Chemogenetics can be employed to selectively modulate the excitability of neurons in vivo 47 . In the current study, we conducted chemogenetic manipulations to activate or inhibit GABAergic neurons in the ACC.…”

Alterations in brain network functional connectivity and topological properties in DRE patients

“…This affects the transmission of information and reduces the degree of synchronization. In addition, due to the lack of effective control of seizures, the patient’s neuronal activity will appear as abnormal synchronicity and rhythmicity ( 13 ). Previous studies have found that different frequency bands are related to the symptoms of patients with epilepsy ( 14 ).…”

“…We utilized the Brain Connectivity Toolbox (BCT) to compute the graph theory metrics of each network ( 13 ). Graph theory metrics are employed to assess the brain network’s small-worldness, i.e., whether it exhibits a high degree of clustering and short characteristic path lengths, features that enhance the efficiency of information transmission within the network.…”

Chemogenetic inhibition of the lateral hypothalamus in rats: A simple but robust tool with high translational relevance to facilitate the development of central nervous system-targeted gene therapies

“…deschloroclozapine, DCZ), the optimization of the generally applied Adeno-Associated Virus (AAV) gene transfer method (virus dose-, titer-, promoter-and serotype selection), the proper toxicological evaluation in the nervous tissue, and the validation of appropriate proof of concept (POC) and " rst in vivo" methods to measure in vivo effectiveness quickly and reliably in rodent behavioral paradigms. Although the generation of in vivo chemogenetic POC studies has been started (e.g., in Parkinson's disease [9][10][11] or epilepsy [12][13][14]), the human translational validity of these pioneering studies is debatable, because of the above detailed methodological aws. Moreover, several high unmet need CNS indications would be potentially suitable targets for chemogenetic drug discovery [2], and more that are completely lacking the proper preclinical in vivo POC studies, including obesity, as a potential future target indication for chemogenetic therapies.…”