Behavioral alterations in the pilocarpine model of temporal lobe epilepsy in mice

Gröticke, Ina; Hoffmann, Katrin; Löscher, Wolfgang

doi:10.1016/j.expneurol.2007.06.021

Cited by 181 publications

(164 citation statements)

References 72 publications

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“…S1A). This ramping protocol has been shown to reduce mortality after SE (10). No differences in the behavioral seizure score were seen between dnSNARE animals and their WT littermates ( Fig.…”

Section: Resultsmentioning

confidence: 85%

Astrocyte control of synaptic NMDA receptors contributes to the progressive development of temporal lobe epilepsy

Clasadonte

Dong

Hines

2013

Proc. Natl. Acad. Sci. U.S.A.

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Astrocytes modulate neuronal activity, synaptic transmission, and behavior by releasing chemical transmitters in a process termed gliotransmission. Whether this process impacts epilepsy in vivo is not known. We show that genetic impairment of transmitter release from astrocytes by the expression of a glial dominantnegative SNARE domain in mice reduced epileptiform activity in situ, delayed seizure onset after pilocarpine-induced status epilepticus, and attenuated subsequent progressive increase in seizure frequency in vivo. The reduced seizure frequency was accompanied by attenuation of hippocampal damage and behavioral deficits. As the delay in seizure onset and the reduced seizure frequency were mimicked by intracerebroventricular delivery of the NMDA receptor (NMDAR) antagonist D-(-)-2-amino-5-phosphonopentanoate in WT littermates and because dominant-negative SNARE expression leads to a hypofunction of synaptic NMDARs, we conclude that astrocytes modulate epileptogenesis, recurrent spontaneous seizures, and pathophysiological consequences of epilepsy through a pathway involving NMDARs.glia-to-neuron signaling | pilocarpine mouse | electroencephalography | hippocampus | interictal spikes T emporal lobe epilepsy (TLE), one of the most common neurological disorders, which affects 1% of the population worldwide, is characterized by the occurrence of recurring unprovoked spontaneous seizures. Unfortunately, seizures in 30% of patients with TLE are not controlled by anticonvulsant agents, drugs that are directed to neuronal targets. In this case, patients may undergo resective epilepsy surgery to become seizure-free (1).Emerging evidence suggests a critical role for the glial cells, astrocytes, in epilepsy (2, 3). Astrocytes play an important role in maintaining central nervous system function by releasing gliotransmitters, including glutamate, D-serine, and ATP (4). Whether gliotransmission contributes to epilepsy in vivo has not been established. It has recently been shown that gliotransmission regulates the trafficking and surface expression of the neuronal N-methyl-D-aspartate receptor (NMDAR) subunits 2A and 2B (5, 6). Because of the importance of NMDARs in epilepsy (7), we hypothesize that astrocytes modulate epileptic seizures by regulating these receptors. To test this hypothesis, we used astrocytespecific molecular genetics in mice to inhibit transmitter release from astrocytes, along with the in vivo pilocarpine model of TLE, long-term continuous video EEG, and an in situ hippocampal slice model of epilepsy.We show that genetic impairment of transmitter release from astrocytes by the expression of glial dominant-negative SNARE (dnSNARE) (8) delayed the onset of spontaneous recurrent seizures (SRSs) and attenuated the progressive increase in frequency of SRSs, hippocampal sclerosis, and the appearance of aberrant open-field behaviors. Similarly, chemically induced epileptiform activity in situ was attenuated by the expression of astrocytic dnSNARE. The ability of dnSNARE to reduce epileptiform activity in...

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Section: Resultsmentioning

confidence: 85%

Astrocyte control of synaptic NMDA receptors contributes to the progressive development of temporal lobe epilepsy

Clasadonte

Dong

Hines

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…To test this hypothesis, we used the muscarinic receptor agonist pilocarpine to unspecifically increase the excitatory level at doses of 100 mg/kg that induce tonic-clonic seizures and status epilepticus in wild-type mice (see Materials and Methods) (Gröticke et al, 2007). We found that COUP-TFI CKO-Dlx5/6 mice (n ϭ 7) were more resistant to seizures and to developing status epilepticus than WT (n ϭ 7), as reflected in both the cortical EEG recordings and clinical manifestations (Fig.…”

Section: Coup-tfi Mutants Are More Resistant To Seizures Induced By Lmentioning

confidence: 99%

Loss of COUP-TFI Alters the Balance between Caudal Ganglionic Eminence- and Medial Ganglionic Eminence-Derived Cortical Interneurons and Results in Resistance to Epilepsy

Lodato¹,

Tomassy²,

Leonibus³

et al. 2011

J. Neurosci.

100

106

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“…This approach is often accompanied by a high mortality rate and does not always lead to SE induction in a satisfactory proportion of animals (Turski et al, 1989;Glien et al, 2001;Buckmaster and Haney, 2012;Mazzuferi et al, 2012). Using a fractionated protocol with repetitive injection of smaller pilocarpine doses can improve the outcome in terms of SE induction rate and low mortality in rats and in mice (Glien et al, 2001;Gröticke et al, 2007;Schauwecker, 2012). Additionally, lithium chloride is often administered the evening before the pilocarpine experiment, which drastically reduces the required pilocarpine dose for SE induction, thereby increasing the proportion of animals surviving SE (Clifford et al, 1987;Bersudsky et al, 1994;Shaldubina et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Pilocarpine-Induced Convulsive Activity Is Limited by Multidrug Transporters at the Rodent Blood-Brain Barrier

Römermann

Löscher

Bankstahl

2015

J Pharmacol Exp Ther

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As a result of the growing availability of genetically engineered mouse lines, the pilocarpine post-status epilepticus (SE) model of temporal lobe epilepsy is increasingly used in mice. A discrepancy in pilocarpine sensitivity in FVB/N wild-type versus P-glycoprotein (PGP)-deficient mice precipitated the investigation of the interaction between pilocarpine and two major multidrug transporters at the blood-brain barrier. Doses of pilocarpine necessary for SE induction were determined in male and female wild-type and PGP-deficient mice. Brain and plasma concentrations were measured following low (30-50 mg×kg 21 i.p.) and/or high (200 mg×kg 21 i.p.) doses of pilocarpine in wild-type mice, and mice lacking PGP, breast cancer resistance protein (BCRP), or both transporters, as well as in rats with or without pretreatment with lithium chloride or tariquidar. Concentration equilibrium transport assays (CETA) were performed using cells overexpressing murine PGP or BCRP. Lower pilocarpine doses were necessary for SE induction in PGP-deficient mice. Brain-plasma ratios were higher in mice lacking PGP or PGP and BCRP, which was also observed after pretreatment with tariquidar in mice and in rats. Lithium chloride did not change brain penetration of pilocarpine. CETA confirmed transport of pilocarpine by PGP and BCRP. Pilocarpine is a substrate of PGP and BCRP at the rodent blood-brain barrier, which restricts its convulsive action. Future studies to reveal whether strain differences in pilocarpine sensitivity derive from differences in multidrug transporter expression levels are warranted.

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Behavioral alterations in the pilocarpine model of temporal lobe epilepsy in mice

Cited by 181 publications

References 72 publications

Astrocyte control of synaptic NMDA receptors contributes to the progressive development of temporal lobe epilepsy

Astrocyte control of synaptic NMDA receptors contributes to the progressive development of temporal lobe epilepsy

Loss of COUP-TFI Alters the Balance between Caudal Ganglionic Eminence- and Medial Ganglionic Eminence-Derived Cortical Interneurons and Results in Resistance to Epilepsy

Pilocarpine-Induced Convulsive Activity Is Limited by Multidrug Transporters at the Rodent Blood-Brain Barrier

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