Metabotropic glutamate receptor mglur1 functional roles in the development and synaptic plasticity in the cerebral cortex

Resumen

Metabotropic glutamate receptors are G protein-coupled receptors that influence diverse cascades of intracellular second messengers that modulate neuronal excitability, synaptic plasticity and neurodegeneration. These receptors also participate in the processes of Ca2+ release and neuronal excitabily that occurs during development and are involved in important pathophysiological processes, including neurodegenerative diseases. The present thesis centers on mGluR1, a member of group I of mGluRs. The first theme of the thesis is the analysis of novel aspects of the functional roles of this receptor during the development of the cerebral cortex. We found expression of the receptor during development in places and ages not described previously in the diencephalon and the telencephalon, as the region surrunding the internal capsule and the ventricular zone of the ganglionic eminences. These places are described as important for the guidance of thalamocortical axons and for the migration of interneurons. We found that the absence of mGluR1 in the guidepost cells surrounding the internal capsule produce alterations in the guidance and navigation of these axons, with possible definitive consequences on the anatomical organization of this axonal system. mGluR1 mutant mice presented signs of increased anxiety and an impaired prepulse inhibition of the startle response. The mgluR1 antagonist BAY36-7620 administered to wild type mice does not mimic these effects, suggesting that these alterations are not a direct consequence of the absence of functional receptor and must be a consequence of the reduction in the number of fast spiking interneurons that we found in hippocampus and prefrontal cortex of mGluR1 mutant mice. We found expression of mGlur1 in the places of origin of interneurons during development. mGluR1 knockout mice display a decreased population of migrating interneurons and impaired migration in in vitro assays, so we propose that mGluR1 may intervene in the genesis or migration of cortical interneurons. A major second theme in this thesis addresses the involvement of mGluR1 in synaptic plasticity. We found that mgluR1 couples associative learning and activity-dependent changes in the CA3-CA1 synapse in alert behaving mice. Moreover mGlur1 is involved in long term potentiation at CA3-CA1 synapse. These functional roles of mGluR1 withing hippocampal circuits, could be tentatively ascribed to a direct postsynaptic effect of mGluR1 on CA1 pyramidal neurons.