Partial depletion of septohippocampal cholinergic cells reduces seizure susceptibility, but does not mitigate hippocampal neurodegeneration in the kainate model of epilepsy

Soares, Joana I.; Costa, Catarina; Ferreira, Maria H.; Andrade, Pedro; Maia, Gisela H.; Lukoyanov, Nikolay

doi:10.1016/j.brainres.2019.04.027

Cited by 5 publications

(3 citation statements)

References 51 publications

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“…5). This theta-rhythm medial septum stimulation has been thought to restore disrupted theta oscillations in the epileptic HPC presumably via cholinergic mechanisms (Colom et al, 2006;Soares et al, 2019). The dual anti-seizure effect roles of the medial septum make it a valuable DBS target for refractory TLE.…”

Section: Discussionmentioning

confidence: 99%

Closed-loop stimulation of the medial septum terminates epileptic seizures

Takeuchi

Harangozó

Pedraza

et al. 2021

Brain

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Temporal lobe epilepsy with distributed hippocampal seizure foci is often intractable and its secondary generalization might lead to sudden death. Early termination through spatially extensive hippocampal intervention is not feasible directly, because of the large size and irregular shape of the hippocampus. In contrast, the medial septum is a promising target to govern hippocampal oscillations through its divergent connections to both hippocampi. Combining this ‘proxy intervention’ concept and precisely timed stimulation, we report here that closed-loop medial septum electrical stimulation can quickly terminate intrahippocampal seizures and suppress secondary generalization in a rat kindling model. Precise stimulus timing governed by internal seizure rhythms was essential. Cell type-specific stimulation revealed that the precisely timed activation of medial septum GABAergic neurons underlaid the effects. Our concept of time-targeted proxy stimulation for intervening pathological oscillations can be extrapolated to other neurological and psychiatric disorders, and has potential for clinical translation.

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Section: Discussionmentioning

confidence: 99%

Closed-loop stimulation of the medial septum terminates epileptic seizures

Takeuchi

Harangozó

Pedraza

et al. 2021

Brain

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“…Interestingly, neurons located in the MCPO, which send only a small number of cholinergic afferents to the amygdala, were not significantly enlarged. Although the importance of cholinergic plasticity in epilepsy is not yet clarified, the results of one study [72] indicate that site-specific inhibition of neuronal hypertrophy in the medial septum reduces seizure susceptibility and partially prevents epileptogenesis in a subset of KA-treated rats. Considered together with the present findings, these data suggest that a more widespread blockage of seizure-driven cholinergic hypertrophy, including in the medial septum and the regions examined in this study, might provide better protection against seizures and epileptogenesis.…”

Section: Discussionmentioning

confidence: 99%

Neuroplasticity in Cholinergic Projections from the Basal Forebrain to the Basolateral Nucleus of the Amygdala in the Kainic Acid Model of Temporal Lobe Epilepsy

Lustosa

Soares

Biagini

et al. 2019

IJMS

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The amygdala is a cerebral region whose function is compromised in temporal lobe epilepsy (TLE). Patients with TLE present cognitive and emotional dysfunctions, of which impairments in recognizing facial expressions have been clearly attributed to amygdala damage. However, damage to the amygdala has been scarcely addressed, with the majority of studies focusing on the hippocampus. The aim of this study was to evaluate epilepsy-related plasticity of cholinergic projections to the basolateral nucleus (BL) of the amygdala. Adult rats received kainic acid (KA) injections and developed status epilepticus. Weeks later, they showed spontaneous recurrent seizures documented by behavioral observations. Changes in cholinergic innervation of the BL were investigated by using an antibody against the vesicular acetylcholine transporter (VAChT). In KA-treated rats, it was found that (i) the BL shrunk to 25% of its original size (p < 0.01 vs. controls, Student’s t-test), (ii) the density of vesicular acetylcholine transporter-immunoreactive (VAChT-IR) varicosities was unchanged, (iii) the volumes of VAChT-IR cell bodies projecting to the BL from the horizontal limb of the diagonal band of Broca, ventral pallidum, and subcommissural part of the substantia innominata were significantly increased (p < 0.05, Bonferroni correction). These results illustrate significant changes in the basal forebrain cholinergic cells projecting to the BL in the presence of spontaneous recurrent seizures.

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“…Regarding the other role, previous studies have shown that open-loop theta (4-8 Hz) MS E-stim reduces seizure susceptibility in animal models (41,42). This theta rhythm MS stimulation has been thought to restore disrupted theta oscillations in the epileptic HPC via presumably cholinergic mechanisms (43,44). The dual roles of the MS for anti-seizure effects make it valuable as a target of DBS for refractory TLE.…”

Section: Ms As a Target Of Dbs In Refractory Tle: Dual Roles In Anti-mentioning

confidence: 99%

Closed-loop stimulation of the medial septum terminates epileptic seizures

Takeuchi

Harangozó

Pedraza

et al. 2020

Preprint

View full text Add to dashboard Cite

Temporal lobe epilepsy with distributed hippocampal seizure foci is often intractable and its secondary generalization might lead to sudden death. Early termination through spatially extensive hippocampal intervention is not feasible directly, due to its large size and irregular shape. In contrast, the medial septum (MS) is a promising target to govern hippocampal oscillations through its divergent connections to both hippocampi. Combining this 'proxy intervention' concept and precisely timed stimulation, we report here that closed-loop MS electrical stimulation can quickly terminate intrahippocampal seizures and suppress secondary generalization in a rat kindling model. Precise stimulus timing governed by internal seizure rhythms was essential. Cell-type-specific stimulation revealed that precisely timed activation of MS GABAergic neurons underlay the effects. Our concept of phase-targeted proxy stimulation for intervening pathological oscillations can be extrapolated to other neurological and psychiatric disorders, and its current embodiment can be directly translated into clinical application.

show abstract

Partial depletion of septohippocampal cholinergic cells reduces seizure susceptibility, but does not mitigate hippocampal neurodegeneration in the kainate model of epilepsy

Cited by 5 publications

References 51 publications

Closed-loop stimulation of the medial septum terminates epileptic seizures

Closed-loop stimulation of the medial septum terminates epileptic seizures

Neuroplasticity in Cholinergic Projections from the Basal Forebrain to the Basolateral Nucleus of the Amygdala in the Kainic Acid Model of Temporal Lobe Epilepsy

Closed-loop stimulation of the medial septum terminates epileptic seizures

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