Introduction: The role of GABAergic interneurons in the context of epilepsy has been largely unexplored. There have been reports that interneurons play a role in cortical synchrony and excessive interneuronal activity is correlated to the generation of interictal spikes and seizures [1,2,3].
Methods: To investigate the potentially causal role of GABAergic neurotransmission in the initiation of interictal spikes and ictal events, we used optogenetic mice expressing channelrhodopsin-2 (ChR2) in inhibitory interneurons.
Results: We found that brief (30 ms) pulses of light evoked either isolated interictal spikes or an interictal spike followed by ictal events in in vitro and in vivo 4-AP seizure model. Whole cell recordings in putative pyramidal cells under 4-AP conditions consistently revealed hyperpolarizing responses to light were followed by rebound spiking and a long lasting membrane depolarization that were both blocked by tetrodotoxin. Gramicidin-perforated patch confirmed there was a hyperpolarizing response to light. The post-inhibitory spiking was confirmed at a larger spatial and cellular scale using multi-electrode array recordings, which revealed a decrease followed by an increase in spike probability similar to what was observed in whole cell recordings. We were able to replicate light-triggered ictal events in other distinct in vitro seizure models (zero Mg2+, and low Mg2+/high K+) and in both the neocortex and hippocampus of mice. We further show that this phenomenon is abolished by GABAA blockade, absent in wild-type mice, and translatable to human neocortical tissue by applying GABA with a picospritzer.
Conclusions: We conclude that optogenetic activation of interneurons can paradoxically initiate ictal events, and that such light-triggered ictal events arise from rebound spiking that follows a light induced hyperpolarization. To our knowledge, we have exploited optogenetic excitation of interneurons to demonstrate for the first time that a robust causal relationship exists between a transient, synchronous release of GABA and onset of ictal activity.
Patient Care: The robust and portable observation that GABAergic discharges can trigger isolated interictal spikes or interictal spikes followed by ictal events suggest that both share the same underlying mechanism involving GABAA receptor activation. The translatability of our observations into human cortical tissue gives clinical relevance to our findings. We demonstrate in human cortical tissue that the proconvulsant nature of GABA under hyperexcitable conditions is an important consideration for the development of new and effective treatments. Current approaches to seizure control are centered on the sole initiative to dampen neuronal excitability through some combination of enhancing GABAergic– or constraining glutamatergic–neurotransmission (White et al., 2007). To some extent, these methods have been effective since they control seizures in approximately two-thirds of individuals with epilepsy (Hesdorffer et al., 2011; Kwan & Brodie, 2000; Mattson et al., 1996). However, the fact remains that nearly one-third of the 50 million people affected by epilepsy worldwide fail to have their seizures controlled by current anti-epileptic drugs (WHO). Our study re-evaluates the transition to seizure with particular emphasis on the underappreciated role of GABAergic neurotransmission as being pro- rather than anti-convulsant.
Learning Objectives: 1. Understand the mechanism underlying seizure initiation
2. Explore the role of GABAergic neurotransmission during seizure onset
3. The paradoxical role of GABA in the neural circuitry
References:  Avoli M, de Curtis M (2011) GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity. Progress in neurobiology 95:104-132.
 Huberfeld G, Menendez de la Prida L, Pallud J, Cohen I, Le Van Quyen M, Adam C, Clemenceau S, Baulac M, Miles R (2011) Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy. Nat Neurosci 14:627-634.
 Pavlov I, Kaila K, Kullmann DM, Miles R (2013) Cortical inhibition, pH and cell excitability in epilepsy: what are optimal targets for antiepileptic interventions? J Physiol 591:765-774.
 White H S, Smith MD, Wilcox KS (2007) Mechanisms of Action of Antiepileptic Drugs. International Review of Neurobiology (Vol. Volume 81, pp. 85-110): Academic Press.
 Hesdorffer DC, Logroscino G, Benn EK, Katri N, Cascino G, Hauser WA (2011) Estimating risk for developing epilepsy: a population-based study in Rochester, Minnesota. Neurology, 76(1):23-27.
 Kwan P, Brodie MJ (2000). Early identification of refractory epilepsy. New England Journal of Medicine, 342(5):314-319.
 Mattson RH, Cramer JA, Collins JF (1996). Prognosis for total control of complex partial and secondarily generalized tonic clonic seizures. Neurology, 47(1):68-76.
 World Health Organization (WHO)