Abstract
Previous studies in rat models of neurodegenerative disorders have shown disregulation of striatal synaptotagmin7 mRNA. Here we explored the expression of synaptotagmin7 mRNA in the brains of rats with seizures triggered by the glutamatergic agonist kainate (10 mg/kg) or by the muscarinic agonist pilocarpine (30 mg/kg) in LiCl (3 mEq/kg) pre-treated (24 h) rats, in a time-course experiment (30 min - 1 day). After kainate-induced seizures, synaptotagmin7 mRNA levels were transiently and uniformly increased throughout the dorsal and ventral striatum (accumbens) at 8 and 12 h, but not at 24 h, followed at 24 h by somewhat variable upregulation within different parts of the cerebral cortex, amigdala and thalamic nuclei, the hippocampus and the lateral septum. By contrast, after LiCl/pilocarpine-induced seizures, there was a more prolonged increase of striatal Synaptotagmin7 mRNA levels (at 8, 12 and 24 h), but only in the ventromedial striatum, while in some other of the aforementioned brain regions there was a decline to below the basal levels. After systemic post-treatment with muscarinic antagonist scopolamine in a dose of 2 mg/kg the seizures were either extinguished or attenuated. In scopolamine post-treated animals with extinguished seizures the striatal synaptotagmin7 mRNA levels (at 12 h after the onset of seizures) were not different from the levels in control animals without seizures, while in rats with attenuated seizures, the upregulation closely resembled kainate seizures-like pattern of striatal upregulation. In the dose of 1 mg/kg, scopolamine did not significantly affect the progression of pilocarpine-induced seizures or pilocarpine seizures-like pattern of striatal upregulation of synaptotagmin7 mRNA. In control experiments, equivalent doses of scopolamine per se did not affect the expression of synaptotagmin7 mRNA. We conclude that here described differential time course and pattern of synaptotagmin7 mRNA expression imply regional differences of pathophysiological brain activation and plasticity in these two models of seizures.
Highlights
Synaptotagmin7 (Syt 7) is a member of the Syt family, which are proteins characterized as essential for synaptic and extrasynaptic membrane trafficking in the brain [1,2,3]
We observed a progressive significant decline of Syt 7 mRNA signal t hat was most prominent at later time points (Figs. 1 and 2)
We used in situ hybridization with a Syt 7 gene specific probe to investigate whether epileptic seizures induced by PI or KA would affect the levels of Syt 7 mRNA in the brain and to investigate some of the possible pharmacological mechanisms underlying the seizure-induced changes of striatal Syt 7 mRNA expression
Summary
Synaptotagmin (Syt 7) is a member of the Syt family, which are proteins characterized as essential for synaptic and extrasynaptic membrane trafficking in the brain [1,2,3]. Superior cervical ganglion neurons explanted from these mice revealed marked defects in neurite outgrowth and arborization, suggesting that Ca2+-dependent, Syt 7-regulated exocytosis of late endosomes/lysosomes plays a role in the addition of new membrane for developing neurite extensions [6]. Antiparkinsonian drugs induced a robust increase in striatal Syt 7 mRNA levels in 6OHDA and reserpinized rats, two established models for Parkinson’s disease, via a dopamine D1 receptor-linked mechanism [9,10]. These results led to the hypothesis that Syt 7 may play a significant role in the effectiveness of antiparkinsonian drugs [9,10]. The exact molecular and pharmacological mechanisms by which changes in striatal Syt 7 expression may be involved in the dopaminergically deafferented striatum remain largely unknown
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