Neuronal and glial pathological changes during epileptogenesis in the mouse pilocarpine model

Borges, Karin; Gearing, Marla; McDermott, Dayna L.; Smith, Amy; Almonte, Antoine G.; Wainer, Bruce H.; Dingledine, Raymond

doi:10.1016/s0014-4886(03)00086-4

Cited by 373 publications

(380 citation statements)

References 52 publications

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“…2) including the hilus of the dentate gyrus, hippocampal subfields CA1 and CA3, different layers of the entorhinal cortex, and the amygdale. Extensive gliosis and atrophy were also noticed in the hippocampus as previously reported (Borges et al, 2003;Liu et al, 1994;Tang et al, 2004). In marked contrast with control rats, chronically epileptic rats exhibited a highly significant reduction in the BK channel immunoreactivity intensity in the hilus of dentate gyrus and CA3 stratum lucidum (Fig.…”

Section: Down-regulation Of Bk Channels In Axons and Terminal Fields supporting

confidence: 81%

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

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In the hippocampus, BK channels are preferentially localized in presynaptic glutamatergic terminals including mossy fibers where they are thought to play an important role regulating excessive glutamate release during hyperactive states. Large conductance calcium-activated potassium channels (BK, MaxiK, Slo) have recently been implicated in the pathogenesis of genetic epilepsy. However, the role of BK channels in acquired mesial temporal lobe epilepsy (MTLE) remains unknown. Here we used immunohistochemistry, laser scanning confocal microscopy (LSCM), western immunoblotting and RT-PCR to investigate the expression pattern of the alpha-pore forming subunit of BK channels in the hippocampus and cortex of chronically epileptic rats obtained by the pilocarpine model of MTLE. All epileptic rats experiencing recurrent spontaneous seizures exhibited a significant down-regulation of BK channel immunostaining in the mossy fibers at the hilus and stratum lucidum of the CA3 area. Quantitative analysis of immunofluorescence signals by LSCM revealed a significant 47% reduction in BK channel in epileptic rats when compared to age-matched non-epileptic control rats. These data correlate with a similar reduction in BK channel protein levels and transcripts in the cortex and hippocampus. Our data indicate a seizure-related down-regulation of BK channels in chronically epileptic rats. Further functional assays are necessary to determine whether altered BK channel expression is an acquired channelopathy or a compensatory mechanism affecting the network excitability in MTLE. Moreover, seizure-mediated BK down-regulation may disturb neuronal excitability and presynaptic control at glutamatergic terminals triggering exaggerated glutamate release and seizures.

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Section: Down-regulation Of Bk Channels In Axons and Terminal Fields supporting

confidence: 81%

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

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“…14,15 Histopathological alterations in this model include neuronal loss, mossy fiber sprouting, and hippocampal sclerosis, thus reproducing characteristics of human TLE. 14, 15 We utilized 1 H nuclear magnetic resonance (NMR) spectroscopy and highpressure liquid chromatography (HPLC) to obtain detailed maps of the metabolite content in cerebral cortex and hippocampal formation (HF) in pilocarpine-SE mice. To be able to determine glucose metabolism, we injected animals with [1,[2][3][4][5][6][7][8][9][10][11][12][13] C]glucose 15 minutes before microwave fixation of the head, and evaluated brain extracts using 13 C NMR spectroscopy and gas chromatography-mass spectrometry (GC-MS).…”

Section: Introductionmentioning

confidence: 72%

“…25 Also, loss of hippocampal pyramidal cells has been demonstrated for this pilocarpine mouse model in most mice at several time points from 3 to 31 days after SE. 15 However, a decrease in glutamate content did not correlate with neuronal loss in the hippocampus of patients with TLE. 26 Reduction in glutamate levels is affected more by impaired cell metabolism, such as altered substrate transport, decreased activity of the TCA cycle, and/or various mitochondrial enzymes, than cell loss.…”

Section: Amino-acid and Neurotransmitter Metabolismmentioning

confidence: 90%

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Brain Mitochondrial Metabolic Dysfunction and Glutamate Level Reduction in the Pilocarpine Model of Temporal Lobe Epilepsy in Mice

Smeland

Hadera

McDonald

et al. 2013

J Cereb Blood Flow Metab

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Although certain metabolic characteristics such as interictal glucose hypometabolism are well established for temporal lobe epilepsy (TLE), its pathogenesis still remains unclear. Here, we performed a comprehensive study of brain metabolism in a mouse model of TLE, induced by pilocarpine-status epilepticus (SE). To investigate glucose metabolism, we injected mice 3.5-4 weeks after SE with [1,2-13 C]glucose before microwave fixation of the head. Using 1 H and 13 C nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry and high-pressure liquid chromatography, we quantified metabolites and 13 C labeling in extracts of cortex and hippocampal formation (HF). Hippocampal levels of glutamate, glutathione and alanine were decreased in pilocarpine-SE mice compared with controls. Moreover, the contents of N-acetyl aspartate, succinate and reduced nicotinamide adenine dinucleotide (phosphate) NAD(P)H were decreased in HF indicating impairment of mitochondrial function. In addition, the reduction in 13 C enrichment of hippocampal citrate and malate suggests decreased tricarboxylic acid (TCA) cycle turnover in this region. In cortex, we found reduced 13 C labeling of glutamate, glutamine and aspartate via the pyruvate carboxylation and pyruvate dehydrogenation pathways, suggesting slower turnover of these amino acids and/or the TCA cycle. In conclusion, mitochondrial metabolic dysfunction and altered amino-acid metabolism is found in both cortex and HF in this epilepsy model. Keywords: 13 C isotope; glutamate; mitochondria; neurometabolism; NMR spectroscopy; temporal lobe epilepsy Journal of Cerebral Blood INTRODUCTIONTemporal lobe epilepsy (TLE) is one of the most common forms of human epilepsy and is associated with a high level of drug resistance among patients. The mechanisms underlying the pathogenesis of TLE still remain unclear, although increasing evidence points to a disturbance in amino-acid neurotransmitter homeostasis and energy metabolism, as well as neuronal injury. Metabolic characteristics of human TLE include interictal glucose hypometabolism and a decrease in the levels of the neuronal marker N-acetyl aspartate (NAA) in the epileptogenic region. 1,2 Increased levels of extracellular glutamate in epileptogenic hippocampi have been reported before and during seizures 3 and interictally. 4 Moreover, it has been suggested that the uptake of glutamate from the extracellular space by astrocytes is slower in the epileptic brain as the expression of glutamine synthetase, the glial enzyme that converts glutamate to glutamine, was decreased in the epileptogenic hippocampi from patients with TLE. 5,6 Changes in brain metabolism in rat models of TLE resemble those reported in human TLE such as interictal glucose hypometabolism demonstrated in lithium-pilocarpine rats, 7 as well as alterations in NAA and glutamate reported in post-status epilepticus (SE) models induced by kainic acid and lithiumpilocarpine. [8][9][10] There are, however, few comprehensive studies on brain metabolism in mouse model...

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“…7. Thus, SE-evoked glutamate release induces rapid neuronal injury, gliosis (Rizzi et al, 2003;Borges et al, 2003;Choi et al, 2007;Lee et al, 2007), and the induction of CREBdependent transcription in both neurons and glial populations . As a CREBtarget gene, IGF-1 expression is upregulated, and actuates cell proliferation via a MAPKdependent mechanism.…”

Section: Discussionmentioning

confidence: 99%

IGF‐1 receptor‐mediated ERK/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus

Choi

Cho

Hoyt

et al. 2008

Glia

133

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Adult progenitor cell proliferation in the subgranular zone (SGZ) of the dentate gyrus is a dynamic process that is modulated by an array of physiological process, including locomotor activity and novel environmental stimuli. In addition, pathophysiological events, such as ischemia and status epilepticus (SE), have been shown to stimulate neurogenesis. Currently, limited information is available regarding the extracellular stimuli, receptors, and downstream intracellular effectors that couple excitotoxic stimulation to progenitor cell proliferation. Here we show that pilocarpineinduced SE triggers a set of signaling events that impinge upon the p42/44 mitogen-activated protein kinase (MAPK) pathway to drive progenitor cell proliferation in the SGZ at 2-days post-SE. Increased proliferation was dependent on insulin-like growth factor-1 (IGF-1), which was localized to activated microglia near the SGZ. Using a combination of techniques, we show that IGF-1 is a CREB-regulated gene and that SE triggered CRE-dependent transcription in microglia at 2-days post-SE. Together, these data identify a potential signaling program that couples SE to progenitor cell proliferation. SE triggers CREB-dependent transcription in reactive microglia. As a CREB-target gene, IGF-1 expression is upregulated, and by 2-days post-SE, IGF-1 triggers MAPK pathway activation in progenitor cells and, in turn, an increase in progenitor cell proliferation.

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Neuronal and glial pathological changes during epileptogenesis in the mouse pilocarpine model

Cited by 373 publications

References 52 publications

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Brain Mitochondrial Metabolic Dysfunction and Glutamate Level Reduction in the Pilocarpine Model of Temporal Lobe Epilepsy in Mice

IGF‐1 receptor‐mediated ERK/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus

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