Abstracts

This abstract has been invited to present during the Basic Science Poster Highlights poster session

Rationale: Seizure freedom remains elusive for millions of patients worldwide despite an abundance of pharmacologic and surgical epilepsy treatments at our disposal. A greater mechanistic understanding of the dynamics underlying seizures, particularly with respect to excitatory and inhibitory networks, may be critical to close this treatment gap. To this end, in vivo two-photon calcium imaging in awake mouse models provides powerful advantages, enabling the repeated acquisition of activity from hundreds of neurons in the intact nervous system with cellular subtype specificity. Using this approach, we characterized the evolution and consistency of excitatory and inhibitory neuronal recruitment during generalized seizures at the cortical microcircuit level, particularly during the pre-ictal to ictal transition and as the seizure progresses through to termination. _x000D_
Methods: Employing a mutually exclusive expression paradigm of two calcium indicators, combined with two-photon microscopy and concurrent EEG, we simultaneously recorded the activity patterns of GABAergic and glutamatergic cortical neurons during pentylenetetrazol-induced seizures (repeated within subject) through chronically implanted cranial windows in awake mice._x000D_
Results: Examining the pre-ictal to ictal transition, we observe simultaneous excitatory and inhibitory cell recruitment concurrent with pre-ictal spiking on EEG. While the majority of neurons are recruited at the same time across the populations, we detected a persistent delay in recruitment of some GABAergic cells compared to glutamatergic cells. With progression toward seizure invasion, we found the delay between the populations increases, with the glutamatergic recruitment becoming more co-incident with the EEG spiking. Furthermore, we observe a trend in desynchronization within these populations ahead of seizure invasion. Taken together these results may suggest an evolving breakdown in inhibitory restraint. Upon seizure termination, preceding a post-ictal phase, we typically observed a slow propagating calcium wave, followed by a sustained decline in calcium signal, consistent with cortical spreading depression. Both GABAergic and glutamatergic soma and neuropil were recruited simultaneously reflecting a likely non-synaptically mediated spread. Additionally, we found these events to have similar spatiotemporal patterns across separate seizure episodes within subject._x000D_
Conclusions: These findings in our generalized model are consistent with dynamics observed in several other seizure models. They suggest that cortical seizure recruitment may follow a conserved pattern of activity independent of the underlying ictogenic mechanism. Such stereotyped activity, particularly during the ictal transition and seizure termination, holds potential to be leveraged in the development and targeting of neuromodulatory epilepsy treatment._x000D_
Funding: NIH NINDS F31NS115479 (MAS), NIH OD S10OD021773 (KB), Mirowski Family Foundation (REG)