Seizure-induced neuronal apoptosis is related to dysregulation of the RNA-edited GluR2 subunit in the developing mouse brain
| Autor: | Carol-Immanuel Geppert, Florian Brackmann, Yili E. Ballheimer, Regina Trollmann, Susan Jung, Daniel Zoglauer, Arndt Hartmann |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Adenosine Deaminase Excitotoxicity Hippocampus Subventricular zone Gene Expression Glutamic Acid Apoptosis AMPA receptor Hippocampal formation Biology medicine.disease_cause Neuroprotection 03 medical and health sciences Mice 0302 clinical medicine Seizures medicine Animals RNA Messenger Receptors AMPA Molecular Biology Neurons General Neuroscience Neurodegeneration Glutamate receptor Age Factors Brain medicine.disease Cell biology Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure nervous system RNA Female Neurology (clinical) Transcriptome 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Brain research. 1735 |
| ISSN: | 1872-6240 |
| Popis: | Ca2+-permeable AMPA receptors (AMPAR) which crucially modify maturational programs of the developing brain are involved in seizure-induced glutamate excitotoxicity and apoptosis. Regulatory effects on AMPAR subunit composition and RNA-editing in the developing brain and their significance as therapeutic targets are not well understood. Here, we analyzed acute effects of recurrent pilocarpine-induced neonatal seizures on age- and region-specific expression of AMPAR subunits and adenosine deaminases (ADAR) in the developing mouse brain (P10). After recurrent seizure activity and regeneration periods of 6–72 h cerebral mRNA levels of GluR (glutamate receptor subunit) 1, GluR2, GluR3, and GluR4 were unaffected compared to controls. However, ratio of GluR2 and GluR4 to pooled GluR1-4 mRNA concentration significantly decreased in seizure-exposed brains in comparison to controls. After a regeneration period of 24–72 h ADAR1 and ADAR2 mRNA expression was significantly lower in seizure-exposed brains than in those of controls. This was confirmed at the protein level in the hippocampal CA3 region. We observed a regionally increased apoptosis (TUNEL+ and CC3+ cells) in the hippocampus, parietal cortex and subventricular zone of seizure-exposed brains in comparison to controls. Together, present in vivo data demonstrate the maturational age-specific, functional role of RNA-edited GluR2 in seizure-induced excitotoxicity in the developing mouse brain. In response to recurrent seizure activity, we observed reduced expression of GluR2 and the GluR2 mRNA-editing enzymes ADAR1 and ADAR2 accompanied by increased apoptosis in a region-specific manner. Thus, AMPA receptor subtype-specific mRNA editing is assessed as a promising target of novel neuroprotective treatment strategies in consideration of age-related developmental mechanisms. |
| Databáze: | OpenAIRE |
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