Direct imaging of hippocampal epileptiform calcium motifs following kainic acid administration in freely behaving mice
Prolonged exposure to abnormally high calcium concentrations is thought to be a core mechanism underlying hippocampal damage in epileptic patients; however, no prior study has characterized calcium activity during seizures in the live, intact hippocampus. We have directly investigated this possibili...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-02-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fnins.2016.00053/full |
| _version_ | 1817991593384214528 |
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| author | Tamara K Berdyyeva E. Paxon eFrady E. Paxon eFrady Jonathan J Nassi Leah eAluisio Yauheniya eCherkas Stephani eOtte Ryan M Wyatt Christine eDugovic Kunal K Ghosh Mark J Schnitzer Timothy eLovenberg Pascal eBonaventure |
| author_facet | Tamara K Berdyyeva E. Paxon eFrady E. Paxon eFrady Jonathan J Nassi Leah eAluisio Yauheniya eCherkas Stephani eOtte Ryan M Wyatt Christine eDugovic Kunal K Ghosh Mark J Schnitzer Timothy eLovenberg Pascal eBonaventure |
| author_sort | Tamara K Berdyyeva |
| collection | DOAJ |
| description | Prolonged exposure to abnormally high calcium concentrations is thought to be a core mechanism underlying hippocampal damage in epileptic patients; however, no prior study has characterized calcium activity during seizures in the live, intact hippocampus. We have directly investigated this possibility by combining whole-brain electroencephalographic (EEG) measurements with microendoscopic calcium imaging of pyramidal cells in the CA1 hippocampal region of freely behaving mice treated with the pro-convulsant kainic acid (KA). We observed that KA administration led to systematic patterns of epileptiform calcium activity: a series of large-scale, intensifying flashes of increased calcium fluorescence concurrent with a cluster of low-amplitude EEG waveforms. This was accompanied by a steady increase in cellular calcium levels (>5 fold increase relative to the baseline), followed by an intense spreading calcium wave characterized by a 218% increase in global mean intensity of calcium fluorescence (n = 8, range [114 - 349%], p<10-4; t-test). The wave had no consistent EEG phenotype and occurred before the onset of motor convulsions. Similar changes in calcium activity were also observed in animals treated with 2 different proconvulsant agents, N-methyl-D-aspartate (NMDA) and pentylenetetrazol (PTZ), suggesting the measured changes in calcium dynamics are a signature of seizure activity rather than a KA-specific pathology. Additionally, despite reducing the behavioral severity of KA-induced seizures, the anticonvulsant drug valproate (VA, 300 mg/kg) did not modify the observed abnormalities in calcium dynamics. These results confirm the presence of pathological calcium activity preceding convulsive motor seizures and support calcium as a candidate signaling molecule in a pathway connecting seizures to subsequent cellular damage. Integrating in vivo calcium imaging with traditional assessment of seizures could potentially increase translatability of pharmacological intervention, leading to novel drug screening paradigms and therapeutics designed to target and abolish abnormal patterns of both electrical and calcium excitation. |
| first_indexed | 2024-04-14T01:15:21Z |
| format | Article |
| id | doaj.art-cd80700a7d014db7a3712e175e7cc9df |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-04-14T01:15:21Z |
| publishDate | 2016-02-01 |
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| series | Frontiers in Neuroscience |
| spelling | doaj.art-cd80700a7d014db7a3712e175e7cc9df2022-12-22T02:20:53ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2016-02-011010.3389/fnins.2016.00053177610Direct imaging of hippocampal epileptiform calcium motifs following kainic acid administration in freely behaving miceTamara K Berdyyeva0E. Paxon eFrady1E. Paxon eFrady2Jonathan J Nassi3Leah eAluisio4Yauheniya eCherkas5Stephani eOtte6Ryan M Wyatt7Christine eDugovic8Kunal K Ghosh9Mark J Schnitzer10Timothy eLovenberg11Pascal eBonaventure12Janssen LLCInscopixUniversity of CaliforniaInscopixJanssen LLCJanssen LLCInscopixJanssen LLCJanssen LLCInscopixInscopixJanssen LLCJanssen LLCProlonged exposure to abnormally high calcium concentrations is thought to be a core mechanism underlying hippocampal damage in epileptic patients; however, no prior study has characterized calcium activity during seizures in the live, intact hippocampus. We have directly investigated this possibility by combining whole-brain electroencephalographic (EEG) measurements with microendoscopic calcium imaging of pyramidal cells in the CA1 hippocampal region of freely behaving mice treated with the pro-convulsant kainic acid (KA). We observed that KA administration led to systematic patterns of epileptiform calcium activity: a series of large-scale, intensifying flashes of increased calcium fluorescence concurrent with a cluster of low-amplitude EEG waveforms. This was accompanied by a steady increase in cellular calcium levels (>5 fold increase relative to the baseline), followed by an intense spreading calcium wave characterized by a 218% increase in global mean intensity of calcium fluorescence (n = 8, range [114 - 349%], p<10-4; t-test). The wave had no consistent EEG phenotype and occurred before the onset of motor convulsions. Similar changes in calcium activity were also observed in animals treated with 2 different proconvulsant agents, N-methyl-D-aspartate (NMDA) and pentylenetetrazol (PTZ), suggesting the measured changes in calcium dynamics are a signature of seizure activity rather than a KA-specific pathology. Additionally, despite reducing the behavioral severity of KA-induced seizures, the anticonvulsant drug valproate (VA, 300 mg/kg) did not modify the observed abnormalities in calcium dynamics. These results confirm the presence of pathological calcium activity preceding convulsive motor seizures and support calcium as a candidate signaling molecule in a pathway connecting seizures to subsequent cellular damage. Integrating in vivo calcium imaging with traditional assessment of seizures could potentially increase translatability of pharmacological intervention, leading to novel drug screening paradigms and therapeutics designed to target and abolish abnormal patterns of both electrical and calcium excitation.http://journal.frontiersin.org/Journal/10.3389/fnins.2016.00053/fullElectroencephalographyKainic Acidseizurecalcium imagingGCaMP6freely behaving mice |
| spellingShingle | Tamara K Berdyyeva E. Paxon eFrady E. Paxon eFrady Jonathan J Nassi Leah eAluisio Yauheniya eCherkas Stephani eOtte Ryan M Wyatt Christine eDugovic Kunal K Ghosh Mark J Schnitzer Timothy eLovenberg Pascal eBonaventure Direct imaging of hippocampal epileptiform calcium motifs following kainic acid administration in freely behaving mice Frontiers in Neuroscience Electroencephalography Kainic Acid seizure calcium imaging GCaMP6 freely behaving mice |
| title | Direct imaging of hippocampal epileptiform calcium motifs following kainic acid administration in freely behaving mice |
| title_full | Direct imaging of hippocampal epileptiform calcium motifs following kainic acid administration in freely behaving mice |
| title_fullStr | Direct imaging of hippocampal epileptiform calcium motifs following kainic acid administration in freely behaving mice |
| title_full_unstemmed | Direct imaging of hippocampal epileptiform calcium motifs following kainic acid administration in freely behaving mice |
| title_short | Direct imaging of hippocampal epileptiform calcium motifs following kainic acid administration in freely behaving mice |
| title_sort | direct imaging of hippocampal epileptiform calcium motifs following kainic acid administration in freely behaving mice |
| topic | Electroencephalography Kainic Acid seizure calcium imaging GCaMP6 freely behaving mice |
| url | http://journal.frontiersin.org/Journal/10.3389/fnins.2016.00053/full |
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