Neuroscience Letters 761 (2021) 136110

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Cerebellar contribution to absence epilepsy

Enes Akyuz a, *, Cansu Ozenen b, Oleh R. Pinyazhko c, d, Olesya B. Poshyvak c,
Leonid S. Godlevsky e, *
a
Department of Biophysics, Faculty of International Medicine, University of Health Sciences, Istanbul, Turkey
b
Bolu Abant Izzet Baysal University, Faculty of Medicine, Bolu, Turkey
c
Pharmacology Department, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine
d
Department of Civilization Diseases and Regenerative Medicine, WSIiZ, Rzeszow, Poland
e
Department of Biophysics, Informatics and Medical Devices, Odesa National Medical University, 2, Valikhovsky Lane, Odesa 65082, Ukraine

A R T I C L E I N F O A B S T R A C T

Keywords: The new aggregate data analyses revealed the earlier missing role of cerebellum long-term electrical stimulation
Absence epilepsy in the absence epilepsy. Neurophysiologic data gained by authors favor that cerebellar serial deep brain stim­
Spike-wave discharges ulation (DBS) (100 Hz) causes the transformation of penicillin-induced cortical focal discharges into prolonged
Cerebellum
3,5–3,75 sec oscillations resembling spike-wave discharges (SWD) in cats. Such SWDs were not organized in the
Deep brain stimulation
Penicillin induced foci
form of bursts and persisted continuously after stimulation. Therefore, the appearance of prolonged periods of
SWD is regarded as a tonic cerebellar influence upon pacemaker of SWD and might be caused by the long-lasting
DBS-induced increase of GABA-ergic extrasynaptic inhibition in the forebrain networks. The absence seizure
facilitation caused by cerebellar DBS was discussed with the reviewed data on optogenetic stimulation, neuronal
activity of cerebellar structures, and imaging data.

Childhood absence epilepsy (CAE) is a benign form of generalized
epilepsy that comprises 10–15% of all childhood epilepsies [1,2]. Both
experimental and clinical absence seizures (AS) represent minimal
visible clinical symptoms and typical and profound EEG deterioration
[3–7].
Main pathogenetic peculiarities of spike-wave discharges (SWDs) as
a biomarker of AS confined to hyperexcitation within the cortico-
thalamocortical (CTC) network [5–8]. Intensively developed in­
vestigations of genetic forms of absence seizures have been performed in
recent decades [9–13]. Calcium channel deterioration may underlie
such a hyperactive state of neurons within the CTC network due to an
α(1A) voltage-sensitive calcium channel gene mutation – as established
in tottering (tg) and tg(la) mice [13–16].
Recent data proved that pathological enhancement of GABAergic
signaling within a thalamocortical network is necessary and sufficient
for nonconvulsive AS development [17–24] (Fig. 2). The overwhelming
inhibitory GABAergic effect is in charge of the absence of SWD promo­
tion [17,18,25]. It might assume that increased activation of
extrasynaptic GABAA receptors (eGABAARs) and augmented tonic
GABAA inhibition in thalamocortical neurons are in charge of such an
effect [19].
Continuously developed absence seizures in rats induced via gamma-
butyrolactone (GHB) (200 mg/kg, i.p.) administration to rats were
characterized by a lower frequency of discharges (2,64–3,59 Hz), not
organized as bursts [23,26]. Enhanced GABAergic inhibition serves as a
basic conception of AS manifestations, and compounds that intensified
GABAergic inhibition are recognized as proabsent compounds [24].
Huguenard J [27] strengthened the reticular thalamic nucleus (RT)’s
leading role in the GABAergic suppression of specific thalamic nuclei.
Such data were in line with the two-phase effects of vigabatrin on SWD
[28] and with the suppression of SWD caused by the deep brain stim­
ulation (DBS) of RT [39].
Despite relatively good pharmacological control of CAE manifesta­
tions, resistance to treatment is actual [30–33]. Searching for alternative
therapy of nonresponsive AS targets for DBS proved promising [34].
Thalamic structures are the first line of such targets [29,34,35], while

Abbreviations: AS, absence seizures; CAE, childhood absence epilepsy; CTC, cortico-thalamo-cortical (network); DBS, deep brain stimulation; EEG, electroen­
cephalogram; eGABAAR, extrasynaptic gamma aminobutyric acid type A receptors; ES, electrical stimulation; GHB, γ-hydroxybutyric acid (butyrolactone); GSWD,
generalized spike-wave discharges; GABA, γ-aminobutyric acid; PC, Purkinje cells; PPC, primary positive component; RT, reticular (thalamic) nucleus; SWD, spike-
wave discharges; [18F]FDG-PET, fludeoxyglucose (18F), positron emission tomography.
* Corresponding authors.
E-mail addresses: enesakyuz25@gmail.com (E. Akyuz), godlevskyleonid@yahoo.com (L.S. Godlevsky).

https://doi.org/10.1016/j.neulet.2021.136110
Received 18 April 2021; Received in revised form 18 May 2021; Accepted 23 June 2021
Available online 10 July 2021
0304-3940/© 2021 Elsevier B.V. All rights reserved.
E. Akyuz et al.
Fig. 2. The figure shows the cortico-thalamocortical pathway. As a biomarker of absence seizure (AS), the main pathogenetic features of spike-wave discharges
(SWDs) are characterized by the cortico-thalamocortical (CTC) network involvement via extrasynaptic GABA receptors activation with GABA synthesized from
excessive glutamate elaborated by cerebellar stimulation.
the cerebellum is almost beyond the scope of interest.
Meanwhile, considering GABA’s role in AS, the question arises
whether the cerebellum could be a source of additional strengthening of
GABAergic mechanisms provoking AS. Expectedly, such a question was
reasonable and justified with data on GABA elaboration from Purkinje
2
Neuroscience Letters 761 (2021) 136110
Fig. 1. Paleocerebellar ES-induced spike-wave activ­
ity in penicillin foci created in the brain cortex of
myorelaxed and artificially ventilated cats (I) and
suppression of slow-wave activity reapplication of
penicillin (II). Notes: Fragment I: A- 17,5 min after the
moment of application of penicillin sodium salt
(16,000 IU/ml) to the posterior sigmoid gyrus; B-1,0
min after the cessation of 2-d ES and 5,5 min after A;
C-5th ES; D-, E- 1,0 min after the moment of 7th ES;
with an arrow, a small amplitude spike preceding a
sharp wave marked. Parameters of ES: 100 Hz, 0,25
ms, 250 mcA (period of ES marked with a solid line at
C). Fragment II: A- 1,5 min from the moment of 8-th
ES of paleocerebellum; B- 0,5 min, C- 2,5 min, and
D- 5,5 min from the new application of benzylpeni­
cillin (16,000 IU/min). (Adopted from 42).
cell (PC) axons and postponed GABA accumulation due to glutamate
metabolism elaborated from nuclei efferents both caused by cerebellar
stimulation [36,37].
To answer this question, we performed investigations on penicillin-
induced models of epilepsy, which can induce SWD [38,39,40].
E. Akyuz et al.
Fig. 3. Cerebellar serial deep brain stimulation causes cortical focal discharges induced by penicillin application to turn into prolonged oscillations that resemble
sharp wave discharges (SWD) in cats.
In our experiments on cats with paleocerebellar stimulation, the
accelerated evolution of penicillin-induced spikes with precipitation of a
large-amplitude primary positive component (PPC) and slow waves
following spikes was observed (Fig. 1, I, B) (Fig. 3) [41]. Such an effect
was registered in 1–2 electrical stimulations (ES), while in control ob­
servations (false stimulated cerebellum) for the appearance of small
amplitude, nonregular PPC needed 15–20 min of spontaneous evolution.
During the next 2–4 ESs, the suppression of spikes along with the
appearance of slightly distorted sinusoidal waves (3,5–3,75/sec) with an
amplitude of 0,45–0,80 mV was registered (Fig. 1, C). The next 2–4 ES
caused spike substitution by relatively regular (3,5–3,75/sec) sinusoidal
waveforms with a constant amplitude of 0,6 to 0,9 mV (Fig. 1, D, E). No
regular small-amplitude spikes preceding the wave were identified
(indicated with an arrow at “E”). It should be stressed that any similar
slow-wave discharge appearance was seen in control observations -
false-stimulated cats with spontaneously declining focal activity.
New local application of penicillin (16,000 IU/ml) in the zone in
which sinusoidal waves were present caused an initial decrease in their
amplitude B) with the appearance of spikes in 1,0–3,0 min . Spike am­
plitudes reached their maximal value in the next 1,0–4,5 min.
Remarkably, PPC was absent in newly appeared discharges.
Similar effects were registered in rats with generalized epilepsy
induced with penicillin administration (300.000 IU/kg, i.p.) when pro­
longed trains of regular SWD (4–5/sec and low amplitude – between 120
and 220 mcV) appeared in the course of paleocerebellar ES. Such ac­
tivity substituted spikes registered in the frontal cortex and coincided
with behavioral signs typical of absence seizure manifestations [42].
Hence, the delivered results revealed that the precipitation of
nonburst-shaped organized prolonged slow waves with frequencies of
3,5–3,75 Hz in the zone of cortical penicillin-induced foci in the cat’s
brain. In rats with generalized penicillin-induced seizures, repeated
paleocerebellar ES caused SWD with a frequency of 4,0–5,0 Hz.
Snead OC et al. [43] delivered data on the appearance of continuous
SWD (3/sec) with unstable spikes caused by GHB (200 mg/kg, i.p.).
Spikes are not regular and might be generated separately (alone) or not
3
Neuroscience Letters 761 (2021) 136110
regularly within rows of slow waves. Additionally, it is essential to note
that in rats, administration of GHB (200 mg/kg, i.p.) resulted in 10–15
min from the moment of administration in continuous SWD with a fre­
quency of 4–5 Hz [44,45].
Such data indicate the net correspondence of GHB-induced activity
with such activity precipitated in the course of paleocerebellar ES in
penicillin-induced models of epilepsy – focal (cats) and generalized
clonic-tonic (rats) models.
The repeated application of penicillin solution abolished slow-wave
activity in the cortical foci. Hence, triggering absence-like slow waves in
the zone of penicillin action upon cortical neurons needs some level of
GABAergic control restoration. This assumption supports pronounced
PPC induction – a marker of surrounding inhibition [46–48] due to
paleocerebellar ES [40,49].
It is worth assuming that the accumulation of GABA in the forebrain
activates eGABAAR δ-containing proteins, which play a critical role in
typical SWD generation in both GHB models and spontaneous AS in
GAER rats [18,50]. The GABA elaboration from PC efferents might be a
source of GABA sufficient for eGABAAR stimulation. Such an assump­
tion is supported by data showing raising GABA levels in cerebrospinal
fluid in the course of high-frequency (200 Hz) ES of the cerebellum
[51,52].
Another source of GABA accumulation is the metabolic conversion of
glutamate released from dentatothalamic pathways [53]. The depolar­
ization of thalamic neurons and dysfacilitation of epileptogenesis are
immediate effects of glutamate, which causes “online” or “phasic” sup­
pression of SWD [36,37]. However, the postponed GABA synthesis is
followed by “off-line” or “tonic” SWD activation. Pharmacological
(gabazine) local stimulation of cerebellar nuclei neuronal activity fol­
lowed by SWD suppression [54] favors the proposed conception.
Different effects of the phasic and tonic effects of cerebellar ES upon
SWD correspond with the suppressive action of intrathalamic adminis­
tration of glutamate receptor agonists upon SWD. In contrast, similar
administration of GABAergic compounds (gamma-vinyl-GABA, tiaga­
bine) stimulates SWD generation in rats with genetic forms of AS
E. Akyuz et al.
[55,56].
Specific changes in extracellular spike trains of cerebellar nuclei of
Cacnala tg mice, another genetic absence model, precipitated in the
course of SWD appearance, prove cerebellum involvement [57]. Up to
26% PC demonstrated an increase in complex spike activity and rhyth­
micity during generalized SWDs in homozygous tottering mice [58]. In
particular, fruitful, almost revolutionary data have been obtained on
optogenetic method applications [59]. Increased cerebellar nuclei im­
pulse activity with optogenetic stimulation immediately suppressed
seizure activity - both generalized spike-wave discharges (GSWD) in
tottering mice [54] and kainic acid-induced hippocampal seizures
[60,61], while suppression caused SWD activation in mice with genetic
forms of absence seizures [54].
Despite the statement made about image data, the cerebellum does
not contribute to absence epilepsy [62,63]; however, later publications
point to such involvement. The thalamus activation and hypo­
metabolism in the frontal, parietal, and posterior cingulate cortices
developed in a parallel fashion with hypermetabolism in the cerebellum
of a patient with absence status epilepticus using the [18F] FDG-PET
method [64]. Blood oxygen level-dependent (response) data on GSWD
activity in patients with juvenile myoclonic epilepsy revealed net cere­
bellum involvement with negative relationships between the thalamus
and cerebellum frontal and sensorimotor-related areas [65,66,67]. In
experiments on tottering mice, Ca2+ imaging revealed PC’s involvement
in GSWD generation [58].
Hence, the presented data favor the modulatory and triggering role
of the cerebellum in AS electrographic manifestations. Such an earlier
missing role may partially contribute to cerebellar DBS inconsistency in
experimental conditions and patients with resistant epilepsy [35,68,69].
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgments
The authors express their thankfulness to Professor Gilles van Luij­
telaar and Professor Coenen A.M.L. for their valuable critical remarks
and recommendations.
Authors contribution
LS developed the conception and wrote the manuscript. C.O. helped
to design figures. POleh and POlesya analyzed the data. E. A. contrib­
uted to final design and edited the manuscript.
Ethics approval
The work was approved by the Ethics Committee of Odesa National
Medical University and conforms to the European Communities Council
Directive 24 November 1986 (86/609/EEC; National Institute of Health
Guide for Care and Use of Laboratory Animals, US National Research
Council, 1996).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.neulet.2021.136110.
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