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Olivocerebellar projections modify hereditary Purkinje cell degeneration
1Francis and Doris Murphy Neuroanatomy Research Laboratory, Department of Anatomy and Neurobiology, and Department of Surgery (Neurosurgery), Saint Louis University School of Medicine, St Louis, MO 63104, USA. tolbertd@slu.edu
Abstract:
Brainstem inferior olivary neurons, through their olivocerebellar efferent projections, dynamically regulate the structure and function of Purkinje neurons. To test the hypothesis that the inferior olive can epigenetically modify adult-onset hereditary Purkinje cell death, olivocerebellar projections were destroyed by 3-acetylpyridine chemoablation of the inferior olive in Shaker mutant rats. Starting around seven weeks of age, mutant Purkinje cells degenerate in a highly predictable spatial and temporal pattern. Chemoablation of the inferior olive at the onset of hereditary Purkinje cell degeneration accelerated the temporal pattern of Purkinje cell death from a natural phenotypic course of six to eight weeks to one and two weeks. When chemoablation of the inferior olive was performed three and a half weeks earlier, the onset of Purkinje cell death was accelerated by seven to 10days, but the spatial pattern and natural rate of temporal degeneration was maintained. Chemoablation of the inferior olive in normal rats did not result in any apparent death of Purkinje cells. These findings indicate that the olivocerebellar system can markedly modify hereditary Purkinje cell death. The accelerated death of Purkinje cells following chemoablation of the inferior olive can result from either the interruption of a trophic signal by climbing fiber deafferentation or parallel fiber excitotoxicity due to cortical disinhibition, but not due to olivocerebellar excitotoxicity.
Insights
The inferior olive influences hereditary Purkinje cell death in Shaker rats. Destroying olivocerebellar projections accelerated cell degeneration, suggesting a role in epigenetic modification of neuronal death.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Brainstem inferior olivary neurons project to the cerebellum, regulating Purkinje neuron structure and function.
- Adult-onset hereditary Purkinje cell death occurs in Shaker mutant rats with a predictable pattern.
- The role of the inferior olive in epigenetic modification of neuronal degeneration is not fully understood.
Purpose of the Study:
- To investigate if the inferior olive epigenetically modifies adult-onset hereditary Purkinje cell death in Shaker mutant rats.
- To determine the impact of olivocerebellar projection integrity on the rate and pattern of Purkinje cell degeneration.
Main Methods:
- 3-acetylpyridine chemoablation was used to destroy olivocerebellar projections in Shaker mutant rats.
- Experiments involved chemoablation at different time points relative to the onset of Purkinje cell degeneration.
- Purkinje cell death was monitored spatially and temporally in both mutant and normal rats.
Main Results:
- Chemoablation of the inferior olive at the onset of degeneration accelerated Purkinje cell death from 6-8 weeks to 1-2 weeks.
- Early chemoablation (3.5 weeks prior) accelerated onset by 7-10 days but maintained spatial pattern and rate.
- Chemoablation in normal rats did not induce Purkinje cell death.
Conclusions:
- The olivocerebellar system significantly modifies hereditary Purkinje cell death.
- Accelerated cell death may result from climbing fiber deafferentation or parallel fiber excitotoxicity, not olivocerebellar excitotoxicity.
- Findings suggest the inferior olive plays a crucial epigenetic role in regulating neuronal survival.