The role of the substantia nigra pars reticulata in kindling resistance in rats with genetic absence epilepsy

Ozlem Akman; Medine I. Gulcebi; Nihan Carcak; Sema Ketenci Ozatman; Tugba Eryigit; Solomon L. Moshé; Aristea S. Galanopoulou; Filiz Yilmaz Onat

doi:10.1111/epi.13204

The role of the substantia nigra pars reticulata in kindling resistance in rats with genetic absence epilepsy

Ozlem Akman, Medine I. Gulcebi, Nihan Carcak, Sema Ketenci Ozatman, Tugba Eryigit, Solomon L. Moshé, Aristea S. Galanopoulou, Filiz Yilmaz Onat

Neurology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Objective Genetic Absence Epilepsy Rats from Strasbourg (GAERS) show a resistance to secondary generalization of focal limbic seizures evoked by kindling. The substantia nigra pars reticulata (SNR) is involved in the propagation and modulation of seizures in kindling. We first examined the role of the SNR_anterior and SNR_posterior subregions in the resistance to the development of kindling in GAERS. Subsequently, to determine whether kindling resistance relates to differential sensitivity of γ-aminobutyric acid γ-aminobutyric acid (GABA)ergic or dopaminergic SNR neurons to kindling, we studied the effects of kindling-inducing stimulations on parvalbumin (PRV; GABAergic neuron marker) or tyrosine hydroxylase (TH; dopaminergic neuron marker) immunoreactivity (ir), respectively, in GAERS and in nonepileptic control (NEC) Wistar rats that lack kindling resistance. Methods Adult male GAERS were implanted with a stimulation electrode in the amygdala, and bilateral injection cannulas for lidocaine or saline injection (30 min before each kindling stimulation until the animals reached three stage 5 seizures or the 22 stimulations) into the SNR_anterior or SNR_posterior. In another experiment, PRV-ir in SNR_anterior and SNR_posterior and TH-ir in SNR_posterior only were densitometrically compared in GAERS-SHAM, NEC-SHAM GAERS-STIM, and NEC-STIM animals (6 kindling stimulations). Results Bilateral SNR_posterior infusions of lidocaine eliminated the kindling resistance and resulted in stage 5 generalized motor seizures in all kindled rats. Bilateral lidocaine infusions in the SNR_anterior failed to alter the kindling resistance in GAERS. PRV-ir in the SNR_posterior was unaltered in GAERS-STIM but increased in NEC-STIM group. Cellular TH-ir in the SNR_posterior significantly increased by kindling stimulations in both NEC-STIM and GAERS-STIM groups. Significance The kindling resistance in GAERS is mediated by the SNR_posterior in a lidocaine-sensitive manner. The insensitivity to kindling stimulation of PRV-ir in SNR_posterior of GAERS but not NEC rats, implicate GABAergic SNR_posterior neurons in kindling resistance. In contrast, the observed stimulation-specific increase in TH-ir in the SNR_posterior is unrelated to kindling resistance.

Original language	English (US)
Pages (from-to)	1793-1802
Number of pages	10
Journal	Epilepsia
Volume	56
Issue number	11
DOIs	https://doi.org/10.1111/epi.13204
State	Published - Nov 2015

Keywords

GAERS
Kindling resistance
Parvalbumin
Substantia nigra pars reticulata
Tyrosine hydroxylase

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1111/epi.13204

Cite this

@article{233a0646f58341e285d6c67b6287b18b,

title = "The role of the substantia nigra pars reticulata in kindling resistance in rats with genetic absence epilepsy",

abstract = "Objective Genetic Absence Epilepsy Rats from Strasbourg (GAERS) show a resistance to secondary generalization of focal limbic seizures evoked by kindling. The substantia nigra pars reticulata (SNR) is involved in the propagation and modulation of seizures in kindling. We first examined the role of the SNRanterior and SNRposterior subregions in the resistance to the development of kindling in GAERS. Subsequently, to determine whether kindling resistance relates to differential sensitivity of γ-aminobutyric acid γ-aminobutyric acid (GABA)ergic or dopaminergic SNR neurons to kindling, we studied the effects of kindling-inducing stimulations on parvalbumin (PRV; GABAergic neuron marker) or tyrosine hydroxylase (TH; dopaminergic neuron marker) immunoreactivity (ir), respectively, in GAERS and in nonepileptic control (NEC) Wistar rats that lack kindling resistance. Methods Adult male GAERS were implanted with a stimulation electrode in the amygdala, and bilateral injection cannulas for lidocaine or saline injection (30 min before each kindling stimulation until the animals reached three stage 5 seizures or the 22 stimulations) into the SNRanterior or SNRposterior. In another experiment, PRV-ir in SNRanterior and SNRposterior and TH-ir in SNRposterior only were densitometrically compared in GAERS-SHAM, NEC-SHAM GAERS-STIM, and NEC-STIM animals (6 kindling stimulations). Results Bilateral SNRposterior infusions of lidocaine eliminated the kindling resistance and resulted in stage 5 generalized motor seizures in all kindled rats. Bilateral lidocaine infusions in the SNRanterior failed to alter the kindling resistance in GAERS. PRV-ir in the SNRposterior was unaltered in GAERS-STIM but increased in NEC-STIM group. Cellular TH-ir in the SNRposterior significantly increased by kindling stimulations in both NEC-STIM and GAERS-STIM groups. Significance The kindling resistance in GAERS is mediated by the SNRposterior in a lidocaine-sensitive manner. The insensitivity to kindling stimulation of PRV-ir in SNRposterior of GAERS but not NEC rats, implicate GABAergic SNRposterior neurons in kindling resistance. In contrast, the observed stimulation-specific increase in TH-ir in the SNRposterior is unrelated to kindling resistance.",

keywords = "GAERS, Kindling resistance, Parvalbumin, Substantia nigra pars reticulata, Tyrosine hydroxylase",

author = "Ozlem Akman and Gulcebi, {Medine I.} and Nihan Carcak and {Ketenci Ozatman}, Sema and Tugba Eryigit and Mosh{\'e}, {Solomon L.} and Galanopoulou, {Aristea S.} and {Yilmaz Onat}, Filiz",

note = "Publisher Copyright: {\textcopyright} 2015 International League Against Epilepsy.",

year = "2015",

month = nov,

doi = "10.1111/epi.13204",

language = "English (US)",

volume = "56",

pages = "1793--1802",

journal = "Epilepsia",

issn = "0013-9580",

publisher = "Wiley-Blackwell",

number = "11",

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T1 - The role of the substantia nigra pars reticulata in kindling resistance in rats with genetic absence epilepsy

AU - Akman, Ozlem

AU - Gulcebi, Medine I.

AU - Carcak, Nihan

AU - Ketenci Ozatman, Sema

AU - Eryigit, Tugba

AU - Moshé, Solomon L.

AU - Galanopoulou, Aristea S.

AU - Yilmaz Onat, Filiz

PY - 2015/11

Y1 - 2015/11

N2 - Objective Genetic Absence Epilepsy Rats from Strasbourg (GAERS) show a resistance to secondary generalization of focal limbic seizures evoked by kindling. The substantia nigra pars reticulata (SNR) is involved in the propagation and modulation of seizures in kindling. We first examined the role of the SNRanterior and SNRposterior subregions in the resistance to the development of kindling in GAERS. Subsequently, to determine whether kindling resistance relates to differential sensitivity of γ-aminobutyric acid γ-aminobutyric acid (GABA)ergic or dopaminergic SNR neurons to kindling, we studied the effects of kindling-inducing stimulations on parvalbumin (PRV; GABAergic neuron marker) or tyrosine hydroxylase (TH; dopaminergic neuron marker) immunoreactivity (ir), respectively, in GAERS and in nonepileptic control (NEC) Wistar rats that lack kindling resistance. Methods Adult male GAERS were implanted with a stimulation electrode in the amygdala, and bilateral injection cannulas for lidocaine or saline injection (30 min before each kindling stimulation until the animals reached three stage 5 seizures or the 22 stimulations) into the SNRanterior or SNRposterior. In another experiment, PRV-ir in SNRanterior and SNRposterior and TH-ir in SNRposterior only were densitometrically compared in GAERS-SHAM, NEC-SHAM GAERS-STIM, and NEC-STIM animals (6 kindling stimulations). Results Bilateral SNRposterior infusions of lidocaine eliminated the kindling resistance and resulted in stage 5 generalized motor seizures in all kindled rats. Bilateral lidocaine infusions in the SNRanterior failed to alter the kindling resistance in GAERS. PRV-ir in the SNRposterior was unaltered in GAERS-STIM but increased in NEC-STIM group. Cellular TH-ir in the SNRposterior significantly increased by kindling stimulations in both NEC-STIM and GAERS-STIM groups. Significance The kindling resistance in GAERS is mediated by the SNRposterior in a lidocaine-sensitive manner. The insensitivity to kindling stimulation of PRV-ir in SNRposterior of GAERS but not NEC rats, implicate GABAergic SNRposterior neurons in kindling resistance. In contrast, the observed stimulation-specific increase in TH-ir in the SNRposterior is unrelated to kindling resistance.

AB - Objective Genetic Absence Epilepsy Rats from Strasbourg (GAERS) show a resistance to secondary generalization of focal limbic seizures evoked by kindling. The substantia nigra pars reticulata (SNR) is involved in the propagation and modulation of seizures in kindling. We first examined the role of the SNRanterior and SNRposterior subregions in the resistance to the development of kindling in GAERS. Subsequently, to determine whether kindling resistance relates to differential sensitivity of γ-aminobutyric acid γ-aminobutyric acid (GABA)ergic or dopaminergic SNR neurons to kindling, we studied the effects of kindling-inducing stimulations on parvalbumin (PRV; GABAergic neuron marker) or tyrosine hydroxylase (TH; dopaminergic neuron marker) immunoreactivity (ir), respectively, in GAERS and in nonepileptic control (NEC) Wistar rats that lack kindling resistance. Methods Adult male GAERS were implanted with a stimulation electrode in the amygdala, and bilateral injection cannulas for lidocaine or saline injection (30 min before each kindling stimulation until the animals reached three stage 5 seizures or the 22 stimulations) into the SNRanterior or SNRposterior. In another experiment, PRV-ir in SNRanterior and SNRposterior and TH-ir in SNRposterior only were densitometrically compared in GAERS-SHAM, NEC-SHAM GAERS-STIM, and NEC-STIM animals (6 kindling stimulations). Results Bilateral SNRposterior infusions of lidocaine eliminated the kindling resistance and resulted in stage 5 generalized motor seizures in all kindled rats. Bilateral lidocaine infusions in the SNRanterior failed to alter the kindling resistance in GAERS. PRV-ir in the SNRposterior was unaltered in GAERS-STIM but increased in NEC-STIM group. Cellular TH-ir in the SNRposterior significantly increased by kindling stimulations in both NEC-STIM and GAERS-STIM groups. Significance The kindling resistance in GAERS is mediated by the SNRposterior in a lidocaine-sensitive manner. The insensitivity to kindling stimulation of PRV-ir in SNRposterior of GAERS but not NEC rats, implicate GABAergic SNRposterior neurons in kindling resistance. In contrast, the observed stimulation-specific increase in TH-ir in the SNRposterior is unrelated to kindling resistance.

KW - GAERS

KW - Kindling resistance

KW - Parvalbumin

KW - Substantia nigra pars reticulata

KW - Tyrosine hydroxylase

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The role of the substantia nigra pars reticulata in kindling resistance in rats with genetic absence epilepsy

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