The effects of tetanus toxin (TeNT) both in the spinal cord, in clinical tetanus, and in the brain, in experimental focal epilepsy, suggest disruption of inhibitory synapses. TeNT is a zinc protease with selectivity for Vesicle Associated Membrane Protein (VAMP; previously synaptobrevin), with a reported selectivity for VAMP2 in rats. We found spatially heterogeneous expression of VAMP1 and VAMP2 in the hippocampus. Inhibitory terminals in stratum pyramidale expressed significantly more VAMP1 than VAMP2, while glutamatergic terminals in stratum radiatum expressed significantly more VAMP2 than VAMP1. Intrahippocampal injection of TeNT at doses that induce epileptic foci cleaved both isoforms in tissue around the injection site. The cleavage was modest at 2 days after injection and more substantial and extensive at 8 and 16 days. Whole-cell recordings from CA1 pyramidal cells close to the injection site, made 8-16 days after injection, showed that TeNT decreases spontaneous EPSC frequency to 38 % of control and VAMP2 immunoreactive axon terminals to 37 %. In contrast, TeNT almost completely abolished both spontaneous and evoked IPSCs while decreasing VAMP1 axon terminals to 45 %. We conclude that due to the functional selectivity of the toxin to the relative sparing of excitatory synaptic transmission shifts the network to pathogenically excitable state causing epilepsy.
- MeSH
- časové faktory MeSH
- chování zvířat MeSH
- epilepsie temporálního laloku * chemicky indukované metabolismus patofyziologie MeSH
- excitační postsynaptické potenciály MeSH
- hipokampus * metabolismus patofyziologie MeSH
- inhibiční postsynaptické potenciály MeSH
- membránový protein 1 asociovaný s vezikuly * metabolismus MeSH
- membránový protein 2 asociovaný s vezikuly * metabolismus MeSH
- modely nemocí na zvířatech MeSH
- mozkové vlny MeSH
- nervový útlum MeSH
- potkani Sprague-Dawley MeSH
- signální transdukce MeSH
- spánkový lalok * metabolismus patofyziologie MeSH
- tetanový toxin * MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
The auxiliary alpha2delta-1 subunit of voltage-gated calcium channels is up-regulated in dorsal root ganglion neurons following peripheral somatosensory nerve damage, in several animal models of neuropathic pain. The alpha2delta-1 protein has a mainly presynaptic localization, where it is associated with the calcium channels involved in neurotransmitter release. Relevant to the present study, alpha2delta-1 has been shown to be the therapeutic target of the gabapentinoid drugs in their alleviation of neuropathic pain. These drugs are also used in the treatment of certain epilepsies. In this study we therefore examined whether the level or distribution of alpha2delta-1 was altered in the hippocampus following experimental induction of epileptic seizures in rats, using both the kainic acid model of human temporal lobe epilepsy, in which status epilepticus is induced, and the tetanus toxin model in which status epilepticus is not involved. The main finding of this study is that we did not identify somatic overexpression of alpha2delta-1 in hippocampal neurons in either of the epilepsy models, unlike the upregulation of alpha2delta-1 that occurs following peripheral nerve damage to both somatosensory and motor neurons. However, we did observe local reorganization of alpha2delta-1 immunostaining in the hippocampus only in the kainic acid model, where it was associated with areas of neuronal cell loss, as indicated by absence of NeuN immunostaining, dendritic loss, as identified by areas where microtubule-associated protein-2 immunostaining was missing, and reactive gliosis, determined by regions of strong OX42 staining.
- MeSH
- antigeny CD11b metabolismus MeSH
- buněčná smrt MeSH
- epilepsie chemicky indukované komplikace patologie MeSH
- fosfopyruváthydratasa metabolismus MeSH
- glióza etiologie MeSH
- hipokampus * metabolismus MeSH
- krysa rodu rattus MeSH
- kyselina kainová toxicita MeSH
- ligace škodlivé účinky MeSH
- modely nemocí na zvířatech MeSH
- neuralgie etiologie komplikace patologie MeSH
- neurotoxiny toxicita MeSH
- potkani Sprague-Dawley MeSH
- proteiny asociované s mikrotubuly metabolismus MeSH
- regulace genové exprese fyziologie účinky léků MeSH
- spinální ganglia * metabolismus MeSH
- tetanový toxin toxicita MeSH
- vápníkové kanály - typ L MeSH
- vápníkové kanály * metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
