Activity of the Lateral Hypothalamus during Genetically Determined Absence Seizures.

Péter Sere,Magor L Lőrincz,Fanni Győri,Nikolett Zsigri,Timea Raffai,Vincenzo Crunelli,Szabina Furdan

doi:10.3390/ijms22179466

Péter Sere, Magor L Lőrincz + Show 5 more

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https://doi.org/10.3390/ijms22179466

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Abstract

(1) Background: Absence seizures (ASs) are sudden, transient lapses of consciousness associated with lack of voluntary movements and generalized 2.5–4 Hz spike-wave discharges (SWDs) in the EEG. In addition to the thalamocortical system, where these pathological oscillations are generated, multiple neuronal circuits have been involved in their modulation and associated comorbidities including the serotonergic system. Neuronal activity in one of the major synaptic input structures to the brainstem dorsal raphé nucleus (DRN), the lateral hypothalamus (LH), has not been characterized. (2) Methods: We used viral tract tracing and optogenetics combined with in vitro and in vivo electrophysiology to assess the involvement of the LH in absence epilepsy in a genetic rodent model. (3) Results: We found that a substantial fraction of LH neurons project to the DRN of which a minority is GABAergic. The LH to DRN projection can lead to monosynaptic iGluR mediated excitation in DRN 5-HT neurons. Neuronal activity in the LH is coupled to SWDs. (4) Conclusions: Our results indicate that a brain area involved in the regulation of autonomic functions and heavily innervating the RN is involved in ASs. The decreased activity of LH neurons during SWDs could lead to both a decreased excitation and disinhibition in the DRN. These results support a long-range subcortical regulation of serotonergic neuromodulation during ASs and further our understanding of the state-dependence of these seizures and some of their associated comorbidities.

Highlights

Absence seizures (ASs) are sudden, transient lapses of consciousness associated with lack of voluntary movements and generalized 2.5–4 Hz spike-wave discharges (SWDs) in the electroencephalogram (EEG) [1]
Given the involvement of the 5-HT system in absence epilepsy and the reciprocal connections between lateral hypothalamus (LH) and dorsal raphé nucleus (DRN), we investigated whether and how LH neuronal activity is influenced by the generalized SWDs that are the stereotypical signature of ictal periods in a validated rodent model of absence epilepsy, the Genetic Absence Epilepsy Rats from
The present experiments clearly demonstrate that: (i) the LH sends functional monosynaptic excitatory projections to the brainstem DRN; (ii) neuronal activity in LH is modulated by the ongoing seizures both at the population level (LFPs) and single units in the RN; and (iii) the most prominent ictal activity change is a decrease in LH neuronal activity

Summary

Introduction

Absence seizures (ASs) are sudden, transient lapses of consciousness associated with lack of voluntary movements and generalized 2.5–4 Hz spike-wave discharges (SWDs) in the electroencephalogram (EEG) [1]. SWDs are generated in the thalamocortical system , but neuromodulatory circuits including the serotonergic [5,6,7], dopaminergic [8], cholinergic [9] and noradrenergic [10,11] systems have been suggested to play a role in these non-convulsive seizures. Selective serotonin reuptake inhibitors (SSRIs) show an antiepileptic effect and the activity of neurons in the main serotonergic nuclei, the brainstem raphe nuclei is correlated with seizures. 5-HT neurons decrease firing during and after convulsive seizures [15], but show increased activity during SWDs in WAG/Rij rats [16]

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