Cerebellar output controls generalized spike‐and‐wave discharge occurrence

Abstract

ObjectiveDisrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike‐and‐wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are anatomically in an advantageous position to disrupt cortical oscillations through their innervation of a wide variety of thalamic nuclei, is effective in controlling absence seizures.MethodsTwo unrelated mouse models of generalized absence seizures were used: the natural mutant tottering, which is characterized by a missense mutation in Cacna1a, and inbred C3H/HeOuJ. While simultaneously recording single CN neuron activity and electrocorticogram in awake animals, we investigated to what extent pharmacologically increased or decreased CN neuron activity could modulate GSWD occurrence as well as short‐lasting, on‐demand CN stimulation could disrupt epileptic seizures.ResultsWe found that a subset of CN neurons show phase‐locked oscillatory firing during GSWDs and that manipulating this activity modulates GSWD occurrence. Inhibiting CN neuron action potential firing by local application of the γ‐aminobutyric acid type A (GABA‐A) agonist muscimol increased GSWD occurrence up to 37‐fold, whereas increasing the frequency and regularity of CN neuron firing with the use of GABA‐A antagonist gabazine decimated its occurrence. A single short‐lasting (30–300 milliseconds) optogenetic stimulation of CN neuron activity abruptly stopped GSWDs, even when applied unilaterally. Using a closed‐loop system, GSWDs were detected and stopped within 500 milliseconds.InterpretationCN neurons are potent modulators of pathological oscillations in thalamocortical network activity during absence seizures, and their potential therapeutic benefit for controlling other types of generalized epilepsies should be evaluated. Ann Neurol 2015;77:1027–1049

Methods of automated absence seizure detection, interference by stimulation, and possibilities for prediction in genetic absence models

“…Given the fact that optogenitc stimulation is a very recent developed technique, the therapeutic potential of it for seizure intervention has only been investigated in a few studies: In a post cortical stroke model, for example, with seizure focus in the somatosensory cortex, transfection of thalamocortical neurons, passing from the VPM to the somatosensory cortex, with a Halorhodopsin, an opsin which silences cellfiring upon stimulation with yellow light, ipsilateral stimulation was reported to successfully disrupt seizures within 1 second after detection and start of stimulation, while seizure duration in untreated animals and sham stimulated animals (where cells were only transfected reporter gene but no with the light sensitive opsin) varied between 10 to 120sec (Paz et al, 2013). Likewise, Kros et al (2015) tranfected neurons of the cerebellar nuclei whith channel rhodopsin 2, a opsin that activates cell firing upon stimulation with blue light in two mouse models of absence epilepsy, and reported successful disruption of SWD within 500ms. (For a more detailed review on the current imployment of optogenetics within the field of epilepsy reseach the reader is referred to Paz and Huguenard, 2015).…”

Seizing Control

“…Targeting PV interneurons contralateral to the site of seizure initiation significantly curtailed seizure activity (Krook-Magnuson and others 2013), and intervening at a site even as remote as the cerebellum could effectively stop seizures originating in the hippocampus (Krook-Magnuson and others 2014). The cerebellum proved to be a powerful seizure “choke-point” in absence epilepsy as well (Kros and others 2015), and in the case of cortical seizures, long-range thalamic projections to the cortex could be targeted to interrupt both electrographic and generalized seizures (Paz and others 2013). These results highlight the feasibility of “remote seizure control,” which could be a useful clinical strategy in cases where the seizure focus is unknown, diffuse, or not surgically approachable.…”

Wireless power transfer and optogenetic stimulation of freely moving rodents

“…Figure 5.2 shows the top view, cross section and the bottom view of these µLED chips. In the experiments that have been performed with a wired setup, the light intensity at the tip of the implanted fiber was 550 ± 50 µW/mm 2 [18]. With a forward voltage of 2.7 V and a current of 5 mA, both 470 nm and 570 nm µLEDs emit more than 6 mW/m 2 of output power [5].…”