Cerebellar granule cells as a model to study mechanisms of neuronal apoptosis or survival in vivo and in vitro

Abstract

Granule cells of the cerebellum constitute the largest homogeneous neuronal population of mammalian brain. Due to their postnatal generation and the feasibility of well characterized primary in vitro cultures, cerebellar granule cells are a model of election for the study of cellular and molecular correlates of mechanisms of survival/apoptosis and neurodegeneration/neuroprotection. The present review mainly deals with recent data on mechanisms and factors promoting survival or apoptotic elimination of cerebellar granule neurons, with a particular focus on the molecular correlates at the level of gene expression and induction of cellular signal pathways. The in vivo development is first analysed with particular reference to the role played by several neurotrophic factors and by the NMDA subtype of glutamate receptor. Then, mechanisms of survival/apoptosis are examined in the model of primary in vitro cultures, where the role of neurotrophins acting on cerebellar granule cells is followed by the large deal of data coming from the paradigm of potassium/serum withdrawal. The role of some key genes of the Bcl family, of some kinase systems and of transcriptional factors is primarily highlighted. Furthermore, the involvement of mitochondria, free radicals and proteases of the caspase family is considered. Finally, the use of cerebellar granule neurons in primary culture to experimentally address the issue of neurodegeneration and pharmacological neuroprotection is considered, with some comments on models at the borderline between necrosis and apoptosis, such as the excitotoxic neuronal damage. The overlapping of cellular signal pathways activated in granule neurons by apparently unrelated stimuli, such as neurotrophins and neurotransmitters/neuromodulators is stressed to put into light the special 'trophic' role played by activity in neurons. Finally, the advantage of designing and performing conceptually equivalent experiments on cerebellar granule neurons during development in vivo and in vitro, is stressed. On the basis of the reviewed material, it is concluded that cerebellar granule neurons have acquired a special position in modern neuroscience as one of the most reliable models for the study of neural development, function and pathology.