| Brain stimulation with low-frequency stimulation (LFS) is emerging as an alternative treatment for refractory epilepsy. Neuromodulation with low-frequency stimulation (LFS) of brain structures other than epileptic focus is effective in inhibiting seizures in animals and patients, whereas selection of targets for LFS requires further investigation. The hippocampal CA3 subfield is a key site in the circuit of seizure generation and propagation. The present study aimed to illustrate the effects of LFS of the CA3 region on seizure acquisition and generalization in amygdaloid kindling model of epilepsy, and the mode-dependent property on amygdala-kindled seizures in Sprague-Dawley rats. In addition, glutamate is a known critical contributor of epileptogenesis and reduction of glutamine synthetase (GS), the key enzyme for glutamate metabolism, is closely related to the established epilepsy, but the role of GS in epileptogenesis remains unclear. Here we also assessed the expression and activity of GS as well as its role in the progression of amygdaloid kindling in rats. Our aims are to elucidate the epileptogenesis from a new point of view and provide experimental evidence for early intervention of epileptogenesis.1 Low-frequency stimulation of the hippocampal CA3 subfield is anti-epileptogenic and anti-ictogenic in rat amygdaloid kindling model of epilepsyWe found that LFS (monophasic square-wave pulses,1 Hz,100μA and 0.1 ms per pulse) of the CA3 region significantly depressed the duration of epileptiform activity and seizure acquisition by retarding progression from focal to generalized seizures (GS). Moreover, GS latency was significantly increased and GS duration was significantly shortened in LFS group demonstrating an inhibition of the severity of GS and the spread of epileptiform activity. Furthermore, LFS prevented the decline of afterdischarge threshold and elevated GS threshold indicating an inhibition of susceptibility to GS. These results suggest that LFS of the hippocampal CA3 subfield is anti-epileptogenic and anti-ictogenic. Neuromodulation of CA3 activity using LFS may be an alternative potential approach for temporal lobe epilepsy treatment.2 Low-frequency stimulation targeting the hippocampal CA3 subfield affects amygdala-kindled generalized seizures in mode-dependent manner in rats.When fully-kindled seizures were achieved by daily electrical stimulation of the amygdala, LFS (15 min train of 0.1 ms pulses at 1 Hz and 100μA) of the CA3 was applied in several modes. Post-treatment with LFS significantly reduced the severity of and susceptibility to evoked seizures, whereas pre-treatment with LFS resulted in a similar but much weaker inhibition of seizures.Prior consecutive daily application of LFS in the absence of kindling stimulation did not reduce subsequent evoked seizures, but abolished the antiepileptic effect of post-treatment. These results indicated that LFS of the CA3 is able to reduce kindled seizures in a mode-dependent manner without cumulative feature. The hippocampal CA3 subfield could be considered as a potential target for epilepsy treatment using LFS, and should be delivered in an appropriate stimulation mode.3 A transient increase of glutamine synthetase in the ipsilateral dentate gyrus is important for epileptogenesis in rat amygdaloid kindling model of epilepsyBoth expression and activity of GS in the ipsilateral dentate gyrus (DG) were upregulated when the kindling seizures progressed to stage 4. Microinjection into the ipsilateral DG of low doses of methionine sulfoximine (MSO 5 or 10μg in 2μ1), a selective inhibitor of GS, just before the overexpression of GS in stage 4, significantly and dose-dependently reduced the severity of and susceptibility to evoked seizures, whereas MSO at a high dose (20μg) aggravated the progression of kindling seizures. Re-administration of 10μg MSO just before the seizures re-progressed to stage 4, consistently reduced the seizures. Microinjection of L-alpha-aminoadipic acid (5μg), a specific toxin for astrocytes, into the ipsilateral DG, produced seizure inhibition similar to that of 10μg MSO. LFS of the CA3 during the kindling process inhibited the upregulation of GS in the ipsilateral DG area. In addition, an increase of GS expression and activity in the cortex was also observed in pentylenetetrazole-kindling. These results convergently suggest that a transient increase of GS expression and activity is closely involved in the pathogenesis of epilepsy. Inhibition of GS to an adequate degree and at the appropriate time may be a potential therapeutic approach to interrupting epileptogenesis and the mechanism may contribute to the anti-epileptogenic effect of LFS in rat amygdaloid kindling model of epilepsy.
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