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Abstract
Brain stimulation is an alternative treatment for epilepsy. However, the neuronal circuits underlying its mechanisms remain obscure. We found that optogenetic activation (1Hz) of entorhinal calcium/calmodulin-dependent protein kinase II α (CaMKIIα)-positive neurons, but not GABAergic neurons, retarded hippocampal epileptogenesis and reduced hippocampal seizure severity, similar to that of entorhinal low-frequency electrical stimulation (LFES). Optogenetic inhibition of entorhinal CaMKIIα-positive neurons blocked the antiepileptic effect of LFES. The channelrhodopsin-2-eYFP labeled entorhinal CaMKIIα-positive neurons primarily targeted the hippocampus, and the activation of these fibers reduced hippocampal seizure severity. By combining extracellular recording and pharmacological methods, we found that activating entorhinal CaMKIIα-positive neurons induced the GABA-mediated inhibition of hippocampal neurons. Optogenetic activation of focal hippocampal GABAergic neurons mimicked this neuronal modulatory effect and reduced hippocampal seizure severity, but the anti-epileptic effect is weaker than that of entorhinal LFES, which may be due to the limited spatial neuronal modulatory effect of focal photo-stimulation. Our results demonstrate a glutamatergic-GABAergic neuronal circuit for LFES treatment of epilepsy, which is mediated by entorhinal principal neurons.
Highlights
Temporal lobe epilepsy (TLE) is one of the most common types of human epilepsy
low-frequency electrical stimulation (LFES) suppressed hippocampal kindled seizures on all three days of stimulation (p b 0.001 for seizure stage and p = 0.029 for afterdischarge duration (ADD) compared to control, n = 6 for both LFES and control groups; two-way analysis of variance (ANOVA) followed by the LSD post hoc test was used; Fig. 1c), while HFS (20 or 50 Hz, 0.3 mA) in the entorhinal cortex (EC) can directly induce seizures (Fig. S3a), which is similar to the kindling phenomenon in the EC (Giacchino et al, 1984)
Photo-activation (20 Hz) attenuated the antiepileptic effect of entorhinal LFES in kindled mice (p b 0.001 for seizure stage and ADD compared to the LFES group, n = 8 for LFS + light group vs n = 7 for LFES group; Kruskal-Wallis followed by the Mann-Whitney U test was used for seizure stage and one-way ANOVA followed by LSD post hoc test was used for ADD; Fig. 4e), which may have been due to photo-activated (20 Hz) entorhinal GABAergic neurons inhibiting entorhinal principal neuron (PN) (Fig. 4b and c)
Summary
Temporal lobe epilepsy (TLE) is one of the most common types of human epilepsy. The seizures associated with TLE typically arise in the hippocampus, and they are often resistant to antiepileptic drugs (Bialer and White, 2010; Schwartzkroin, 1994). Recurrent uncontrolled hippocampal seizures can result in learning and memory impairments (Lin et al, 2012) as well as sudden unexpected death in TLE patients (Espinosa et al, 2009). Surgical resection of the epileptic focus may abolish hippocampal seizures, this approach is limited by the strict requirements for surgical selection, the risk of cognitive impairment (Bonelli et al, 2013), and the high recurrence rate for seizures. Clinical translation of brain stimulation techniques requires an understanding of its underlying mechanisms, especially because electrical stimulation at specific brain areas can induce memory impairment (Coleshill et al, 2004), undesirable emotional responses (Lanteaume et al, 2007; Liu et al, 2012), and neuroendocrine disorders (Fink and Jamieson, 1974)
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