Российская академия наук


THE ROLE OF METABOTROPIC GLUTAMATE RECEPTORS IN MECHANISMS OF EXCITOTOXICITY Arkhipov V.I



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THE ROLE OF METABOTROPIC GLUTAMATE RECEPTORS IN MECHANISMS OF EXCITOTOXICITY
Arkhipov V.I.
1, Gordon R.Ya.2, Kapralova M.V.1, Ozoline O.N.2, Tutukina M.N.2
1- Federal State Institution of Science Institute of Theoretical and Experimental Biophysics, Pushchino, Russia; 2- Federal State Institution of Science Institute of Cell Biophysics, Pushchino, Russia; viarkhipov@rambler.ru
Metabotropic glutamate receptors (mGlu receptors), both presynaptic and postsynaptic, are capable regulate the efficiency of glutamate and GABA-ergic synaptic transmission. One can assume that excitotoxicity, which contributes significant part to the pathogenesis of many neurodegenerative diseases, can be reduced by modulating the activity of mGlu receptors. In present work, this possibility was investigated by the use kainate experimental model, when kainic acid injected into the dorsal hippocampus of Wistar rats bilaterally (0.2 micrograms). After 2 weeks, as shown by morphological studies, there was cell death in the dorsal hippocampus, mainly in the CA3 field. At the same, the animals showed disorders of memory processes, which are to reduce learning ability, memory retrieval defects and difficulty of learning task extinction. Over time, neurodegeneration continued, and 4 weeks after kainate microinjection neuronal death was observed not only in the CA3, but also in fields CA1 and CA4. The degree of cognitive processes impairment still remains in rats at about the same level as that was in 2 weeks. Expression of mGlu receptors (mGlu2-5) in the hippocampus and frontal cortex areas were determined by qPCR, suggesting that increased levels of gene expression reflects the need for further activation of the receptors, and the reduced level - to suppress their activity. The result revealed that there is the activation of mGlu2 and mGlu4 receptors; at the same time for the mGlu5 receptor trend is the opposite: their expression was reduced one week after microinjection of kainate. Based on this gene expression, 5 days after microinjection of kainate the pharmacological treatment was initiated. mGlu5 receptor antagonist MPEP (2 days, 5 mg/kg, i.p.) with mGlu2 receptor agonist LY354740 (5 days, 2 mg/kg, i.p.) led to a marked decrease in neuronal death, it was localized only in the CA3 hippocampus. Cognitive impairment in these animals persisted; their training was delayed with respect to the control rats.

Thus, the results showed that a reorganization of neuronal networks after hippocampal damage with kainate takes place not only in the hippocampus, but in frontal neocortex also. The level expression of mGlu receptors could be the basis of effective pharmacological treatment during neurodegeneration with help of modulators of the receptors. Supported by RFBR № 12-04-00470.




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