| 1. |
- Kokaia, Merab, et al.
(författare)
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Suppressed epileptogenesis in BDNF mutant mice
- 1995
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 133:2, s. 215-224
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Tidskriftsartikel (refereegranskat)abstract
- Kindling is an animal model of epilepsy in which repeated electrical stimulations lead to progressive and permanent amplification of seizure activity, culminating in generalized convulsions. Each brief period of seizure activity during kindling epileptogenesis causes a marked, transient increase of the synthesis of brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons. We find that the development of kindling is markedly suppressed in mice heterozygous for a deletion of the BDNF gene. In contrast, the maintenance of kindling is unaffected. The mutant mice show lower levels of BDNF mRNA in cortical and hippocampal neurons after seizures than do wild-type mice. Hippocampal mossy fiber sprouting is augmented in BDNF mutants but there are no other morphological abnormalities. These results show that BDNF plays an important role in establishing hyperexcitability during epileptogenesis, probably by increasing efficacy in stimulated synapses.
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| 2. |
- Kokaia, Zaal, et al.
(författare)
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Regulation of brain-derived neurotrophic factor gene expression after transient middle cerebral artery occlusion with and without brain damage
- 1995
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 136:1, s. 73-88
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Tidskriftsartikel (refereegranskat)abstract
- Levels of mRNA for c-fos, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), TrkB, and TrkC were studied using in situ hybridization in the rat brain at different reperfusion times after unilateral middle cerebral artery occlusion (MCAO). Short-term (15 min) MCAO, which does not cause neuronal death, induced elevated BDNF mRNA expression confined to ipsilateral frontal and cingulate cortices outside the ischemic area. With a longer duration of MCAO (2 h), which leads to cortical infarction, the increase was more marked and elevated BDNF mRNA levels were also detected bilaterally in dentate granule cells and CA1 and CA3 pyramidal neurons. Maximum expression was found after 2 h of reperfusion. At 24 h BDNF mRNA expression had returned to control values. In the ischemic core of the parietal cortex only scattered neurons were expressing high levels of BDNF mRNA after 15 min and 2 h of MCAO. Analysis of different BDNF transcripts showed that MCAO induced a marked increase of exon III mRNA but only small increases of exon I and II mRNAs in cortex and hippocampus. In contrast to BDNF mRNA, elevated expression of c-fos mRNA was observed in the entire ipsilateral cerebral cortex, including the ischemic core, after both 15 min and 2 h of MCAO. Two hours of MCAO also induced transient, bilateral increases of NGF and TrkB mRNA levels and a decrease of NT-3 mRNA expression, confined to dentate granule cells. The upregulation of BDNF mRNA expression in cortical neurons after MCAO is probably triggered by glutamate through a spreading depression-like mechanism. The lack of response of the BDNF gene in the ischemic core may be due to suppression of signal transduction or transcription factor synthesis caused by the ischemia. The observed pattern of gene expression after MCAO agrees well with a neuroprotective role of BDNF in cortical neurons. However, elevated levels of NGF and BDNF protein could also increase synaptic efficacy in the postischemic phase, which may promote epileptogenesis.
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