Modulation of epileptogenesis: A paradigm for the integration of enzyme-based microelectrode arrays and optogenetics

Corwin R. Butler, Jeffery A. Boychuk, Francois Pomerleau, Ramona Alcala, Peter Huettl, Yi Ai, Johan Jakobsson, Sidney W. Whiteheart, Greg A. Gerhardt, Bret N. Smith, John T. Slevin

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Background: Genesis of acquired epilepsy includes transformations spanning genetic-to- network-level modifications, disrupting the regional excitatory/inhibitory balance. Methodology concurrently tracking changes at multiple levels is lacking. Here, viral vectors are used to differentially express two opsin proteins in neuronal populations within dentate gyrus (DG) of hippocampus. When activated, these opsins induced excitatory or inhibitory neural output that differentially affected neural networks and epileptogenesis. In vivo measures included behavioral observation coupled to real-time measures of regional glutamate flux using ceramic-based amperometric microelectrode arrays (MEAs). Results: Using MEA technology, phasic increases of extracellular glutamate were recorded immediately upon application of blue light/488 nm to DG of rats previously transfected with an AAV 2/5 vector containing an (excitatory) channelrhodopsin-2 transcript. Rats receiving twice-daily 30-sec light stimulation to DG ipsilateral to viral transfection progressed through Racine seizure stages. AAV 2/5 (inhibitory) halorhodopsin-transfected rats receiving concomitant amygdalar kindling and DG light stimuli were kindled significantly more slowly than non-stimulated controls. In in vitro slice preparations, both excitatory and inhibitory responses were independently evoked in dentate granule cells during appropriate light stimulation. Latency to response and sensitivity of responses suggest a degree of neuron subtype-selective functional expression of the transcripts. Conclusions: This study demonstrates the potential for coupling MEA technology and optogenetics for real-time neurotransmitter release measures and modification of seizure susceptibility in animal models of epileptogenesis. This microelectrode/optogenetic technology could prove useful for characterization of network and system level dysfunction in diseases involving imbalanced excitatory/inhibitory control of neuron populations and guide development of future treatment strategies.

Original languageEnglish (US)
Article number106244
JournalEpilepsy Research
Volume159
DOIs
StatePublished - Jan 2020
Externally publishedYes

Keywords

  • Dentate gyrus
  • Epileptogenesis
  • Glutamate
  • Microelectrode array
  • Optogenetics

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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    Butler, C. R., Boychuk, J. A., Pomerleau, F., Alcala, R., Huettl, P., Ai, Y., Jakobsson, J., Whiteheart, S. W., Gerhardt, G. A., Smith, B. N., & Slevin, J. T. (2020). Modulation of epileptogenesis: A paradigm for the integration of enzyme-based microelectrode arrays and optogenetics. Epilepsy Research, 159, [106244]. https://doi.org/10.1016/j.eplepsyres.2019.106244