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

ABSTRACT: 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 dominant-negative 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.

SUBMITTER: Clasadonte J

PROVIDER: S-EPMC3808607 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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

Clasadonte Jerome J Dong Jinghui J Hines Dustin J DJ Haydon Philip G PG

Proceedings of the National Academy of Sciences of the United States of America 20131007 43

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 dominant-negative SNARE domain in mice reduced epileptiform activity in situ, delayed seizure onset after pilocarpine-induced status epilepticus, and attenuated subsequent progressive increase ...[more]

PMID: 24101472

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Project description:Focal epilepsy in adults is associated with progressive atrophy of the cortex at a rate more than double that of normal ageing. We aimed to determine whether successful epilepsy surgery interrupts progressive cortical thinning. In this longitudinal case-control neuroimaging study, we included subjects with unilateral temporal lobe epilepsy (TLE) before (n = 29) or after (n = 56) anterior temporal lobe resection and healthy volunteers (n = 124) comparable regarding age and sex. We measured cortical thickness on paired structural MRI scans in all participants and compared progressive thinning between groups using linear mixed effects models. Compared to ageing-related cortical thinning in healthy subjects, we found progressive cortical atrophy on vertex-wise analysis in TLE before surgery that was bilateral and localized beyond the ipsilateral temporal lobe. In these regions, we observed accelerated annualized thinning in left (left TLE 0.0192 ± 0.0014 versus healthy volunteers 0.0032 ± 0.0013 mm/year, P < 0.0001) and right (right TLE 0.0198 ± 0.0016 versus healthy volunteers 0.0037 ± 0.0016 mm/year, P < 0.0001) presurgical TLE cases. Cortical thinning in these areas was reduced after surgical resection of the left (0.0074 ± 0.0016 mm/year, P = 0.0006) or right (0.0052 ± 0.0020 mm/year, P = 0.0006) anterior temporal lobe. Directly comparing the post- versus presurgical TLE groups on vertex-wise analysis, the areas of postoperatively reduced thinning were in both hemispheres, particularly, but not exclusively, in regions that were affected preoperatively. Participants who remained completely seizure-free after surgery had no more progressive thinning than that observed during normal ageing. Those with postoperative seizures had small areas of continued accelerated thinning after surgery. Thus, successful epilepsy surgery prevents progressive cortical atrophy that is observed in TLE and may be potentially neuroprotective. This effect was more pronounced in those who remained seizure-free after temporal lobe resection, normalizing the rate of atrophy to that of normal ageing. These results provide evidence of epilepsy surgery preventing further cerebral damage and provide incentives for offering early surgery in refractory TLE.

Project description:ObjectiveIt remains unclear whether drug-resistant temporal lobe epilepsy (TLE) is associated with cumulative brain damage, with no expert consensus and no quantitative syntheses of the available evidence.MethodsWe conducted a systematic review and meta-analysis of MRI studies on progressive atrophy, searching PubMed and Ovid MEDLINE databases for cross-sectional and longitudinal quantitative MRI studies on drug-resistant TLE.ResultsWe screened 2,976 records and assessed eligibility of 248 full-text articles. Forty-two articles met the inclusion criteria for quantitative evaluation. We observed a predominance of cross-sectional studies, use of different clinical indices of progression, and high heterogeneity in age-control procedures. Meta-analysis of 18/1 cross-sectional/longitudinal studies on hippocampal atrophy (n = 979 patients) yielded a pooled effect size of r = -0.42 for ipsilateral atrophy related to epilepsy duration (95% confidence interval [CI] -0.51 to -0.32; p < 0.0001; I2 = 65.22%) and r = -0.35 related to seizure frequency (95% CI -0.47 to -0.22; p < 0.0001; I2 = 61.97%). Sensitivity analyses did not change the results. Narrative synthesis of 25/3 cross-sectional/longitudinal studies on whole brain atrophy (n = 1,504 patients) indicated that >80% of articles reported duration-related progression in extratemporal cortical and subcortical regions. Detailed analysis of study design features yielded low to moderate levels of evidence for progressive atrophy across studies, mainly due to dominance of cross-sectional over longitudinal investigations, use of diverse measures of seizure estimates, and absence of consistent age control procedures.ConclusionsWhile the neuroimaging literature is overall suggestive of progressive atrophy in drug-resistant TLE, published studies have employed rather weak designs to directly demonstrate it. Longitudinal multicohort studies are needed to unequivocally differentiate aging from disease progression.

Project description:PurposeTo examine the effects of current shunt on rats with temporal lobe epilepsy and neocortex epilepsy.Experimental designA kainic acid (KA)-induced model of temporal lobe seizure and a penicillin-induced model of neocortical partial seizure were used in this study. Rats of each model were randomly allocated into two groups: control and model groups. The model group was further divided into the KA or penicillin group, sham conduction group and conduction group. The current shunt was realized through the implantation of a customized conduction electrode. After surgery, electroencephalogram (EEG) was recorded for two hours for each rat under anesthesia. Subsequently, the rats were video monitored for 72 h to detect the occurrence of behavioral seizures upon awakening. The average number and duration of seizures on EEG and the number of behavioral seizures were measured.ResultsIn KA model, the number of total EEG seizures in conduction group (9.57±2.46) was significantly less than that in sham conduction group (15.13±3.45) (p<0.01). The duration of EEG seizures in conduction group (26.13±7.81 s) was significantly shorter than that in sham conduction group (34.17±7.25 s) (p?=?0.001). A significant reduction of behavioral seizures was observed in the conduction group compared with KA (p?=?0.000) and sham conduction groups (p?=?0.000). In penicillin model, there was a 61% reduction in total EEG seizures in conduction group compared with sham conduction group (p<0.01), and the duration of EEG seizures in conduction group (6.29±2.64 s) was significantly shorter than that in the sham conduction group (12.07±3.81 s) (p?=?0.002). A significant reduction of behavioral seizures was observed in conduction group compared with penicillin (p<0.01) and sham conduction groups (p<0.01).ConclusionCurrent shunt effectively reduces the onset and severity of seizures. Current shunt therapy could be an effective alternative minimally invasive approach for temporal lobe epilepsy and neocortex epilepsy.

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

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

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