Temporal lobe epilepsy is the most common type of epilepsy in adults, is often medically refractory, and due to broad actions and long-time scales, current systemic treatments have major negative side-effects. However, temporal lobe seizures tend to arise from discrete regions before overt clinical behaviour, making temporally and spatially specific treatment theoretically possible. Here we report the arrest of spontaneous seizures using a real-time, closed-loop, response system and in vivo optogenetics in a mouse model of temporal lobe epilepsy. Either optogenetic inhibition of excitatory principal cells, or activation of a subpopulation of GABAergic cells representing <5% of hippocampal neurons, stops seizures rapidly upon light application. These results demonstrate that spontaneous temporal lobe seizures can be detected and terminated by modulating specific cell populations in a spatially restricted manner. A clinical approach built on these principles may overcome many of the side-effects of currently available treatment options.

Temporal lobe epilepsy is often medically refractory and new targets for intervention are needed. We used a mouse model of temporal lobe epilepsy, on-line seizure detection, and responsive optogenetic intervention to investigate the potential for cerebellar control of spontaneous temporal lobe seizures. Cerebellar targeted intervention inhibited spontaneous temporal lobe seizures during the chronic phase of the disorder. We further report that the direction of modulation as well as the location of intervention within the cerebellum can affect the outcome of intervention. Specifically, on-demand optogenetic excitation or inhibition of parvalbumin-expressing neurons, including Purkinje cells, in the lateral or midline cerebellum results in a decrease in seizure duration. In contrast, a consistent reduction in spontaneous seizure frequency occurs uniquely with on-demand optogenetic excitation of the midline cerebellum, and was not seen with intervention directly targeting the hippocampal formation. These findings demonstrate that the cerebellum is a powerful modulator of temporal lobe epilepsy, and that intervention targeting the cerebellum as a potential therapy for epilepsy should be revisited.

Key pointsr A key mechanistic concept in epilepsy is the dentate gate hypothesis, which argues that the dentate gyrus protects hippocampal circuits from overexcitation and that a breakdown of this gate leads to epilepsy.r Direct in vivo evidence for the dentate gate hypothesis is lacking and it is therefore unclear whether interventions selectively targeting the dentate gyrus would inhibit seizures.r We demonstrate that on-demand optogenetic restoration of the dentate gate through selective inhibition of granule cells is sufficient to inhibit spontaneous seizures in a mouse model of temporal lobe epilepsy.r By contrast, activation of granule cells worsens spontaneous seizures and can even induce acute seizures in non-epileptic animals.r These data provide direct evidence for the dentate gate hypothesis, indicate that the dentate gyrus is indeed a critical node in temporal lobe seizure circuitry, and illustrate that the dentate gyrus can be an effective target for seizure inhibition.Abstract The dentate gyrus is a region subject to intense study in epilepsy because of its posited role as a 'gate' , acting to inhibit overexcitation in the hippocampal circuitry through its unique synaptic, cellular and network properties that result in relatively low excitability. Numerous changes predicted to produce dentate hyperexcitability are seen in epileptic patients and animal models. However, recent findings question whether changes are causative or reactive, as well as the pathophysiological relevance of the dentate in epilepsy. Critically, direct in vivo modulation of dentate 'gate' function during spontaneous seizure activity has not been explored. Therefore, using a mouse model of temporal lobe epilepsy with hippocampal sclerosis, a closed-loop system and selective optogenetic manipulation of granule cells during seizures, we directly tested the dentate 'gate' hypothesis in vivo. Consistent with the dentate gate theory, optogenetic gate restoration through granule cell hyperpolarization efficiently stopped spontaneous seizures. By contrast, optogenetic activation of granule cells exacerbated spontaneous seizures. Furthermore, activating granule cells in non-epileptic animals evoked acute seizures of increasing severity. These data indicate that the dentate gyrus is a critical node in the temporal lobe seizure network, and provide the first in vivo support for the dentate 'gate' hypothesis.

Fast spiking, parvalbumin (PV) expressing hippocampal interneurons are classified into basket, axo-axonic (chandelier), and bistratified cells. These cell classes play key roles in regulating local circuit operations and rhythmogenesis by releasing GABA in precise temporal patterns onto distinct domains of principal cells. In this study, we show that each of the three major PV cell classes further splits into functionally distinct sub-classes during fast network events in vivo. During the slower (<10 Hz) theta oscillations, each cell class exhibited its own characteristic, relatively uniform firing behavior. However, during faster (>90 Hz) oscillations, within-class differences in PV interneuron discharges emerged, which segregated along specific features of dendritic structure or somatic location. Functional divergence of PV sub-classes during fast but not slow network oscillations effectively doubles the repertoire of spatio-temporal patterns of GABA release available for rapid circuit operations.DOI: http://dx.doi.org/10.7554/eLife.04006.001

Optogenetic interventions offer novel ways of probing, in a temporally specific manner, the roles of specific cell types in neuronal network functions of awake, behaving animals. Despite the unique potential for temporally specific optogenetic interventions in disease states, a major hurdle in its broad application to unpredictable brain states in a laboratory setting is constructing a real-time responsive system. We recently created a closed-loop system for stopping spontaneous seizures in chronically epileptic mice using optogenetic intervention. This system performs with very high sensitivity and specificity, and the strategy is relevant not only to epilepsy, but can also be used to react in real time, with optogenetic or other interventions, to diverse brain states. The protocol presented here is highly modular and requires variable time to perform. We describe the basic construction of a complete system, and include our downloadable custom closed-loop detection software which can be employed for this purpose.