ABSTRACT

The aims of the PhD project were to investigate the role of group I metabotropic glutamate receptors (mGluR1 and mGluR5) in glutamate receptor-mediated neurodegeneration, including the effects of the individual receptors and the underlying mechanisms.

The studies were performed on organotypic slice cultures of the rat hippocampus. The induced neurodegeneration of CA1 pyramidal cells was monitored by recording the cellular uptake of the fluorescent dye propidium iodide, supplemented by different immunohistochemical markers like loss of microtubule associated protein and changes in nuclei morphology. Changes in gene expressions were monitored by means of cDNA microarrays.

The results show that activation of mGluRs can induce, potentiate and protect against neurodegeneration dependent on the timing of agonist application. Activation of the receptors during the neurodegenerative insult (application of N-Methyl-D-aspartate; NMDA) will thus lead to a potentiation of neuronal cell death, whereas activation of receptors prior to the insult was neuroprotective. The induced neuroprotection was associated with a reduction in NMDA-stimulated inward current (measured by electrophysiology) suggesting that NMDA-receptors were compromised. Changes were recorded in the expression of 33 genes, of which 14 could be associated with neuroprotection. One particular gene, Rab5b, emerged as a candidate for neuroprotection because this gene is essential for endocytosis, and its upregulation could potentially cause internalisation of NMDA-receptors with resulting neuroprotection. Moreover, inhibition of the group I mGluRs also protected neurons in an experimental model of cerebral ischaemia, based on oxygen and glucose deprivation. It is concluded that group I mGluRs dependent on the timing of activation have different effects on neurodegeneration and thus could be interesting targets for modulation of nerve cell death after cerebral ischaemia.