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Key molecule in the elusive regeneration of cerebellum synaptic connections identified.

It is known that nerves in the central nervous system of adult mammals do not usually regenerate when injured.  However, the granule cell, a nerve cell located in the cerebellum, is different. When its fibres, called parallel fibres, are cut, rapid regeneration ensues and junctions with other neurons called synapses are rebuilt; the precise mechanism for which is unclear.  Now, a study from researchers led by Hokkaido University shows that the glutamate receptor, GluD2, expressed at these parallel fibres regulates the regeneration of the synapses.  The team state that their findings show that shutting down the gene that encodes GluD2 results in a severe reduction in these synapses.  The study is published in The Journal of Neuroscience.

Previous studies show that GluD2 is a receptor located at the receiving end of the synapse, where the granule cell parallel fibres meet with another nerve cell type called the Purkinje cell, which is also present in the cerebellum. Nerve impulses pass via chemical mediators from one nerve fibre to another through synapses. The granule cell-Purkinje cell synapse, in particular, is where the regeneration occurs.  The current study shows that the GluD2 receptor is involved in maintaining the synapses between granule cell parallel fibres and Purkinje cell nerve fibres.

The current study investigated the effects of cutting parallel fibres in normal mice and in mice that lack the GluD2 receptor. They examined serial sections of the cerebellum under a microscope, and reconstructed three-dimensional images of parallel fibre synapses on Purkinje cells one, seven and 30 days after the incisions were made.  Results show that the cut parallel fibres in normal mice underwent three distinct phases.

Data findings show that in the first degeneration phase, the number of parallel fibres and synapses was halved; in the second hypertrophy phase, the number of parallel fibres remained the same, undergoing thickening and enlarging of their terminals; and in the final remodeling phase, the number of parallel fibres were recovered and the thickening and enlargement that occurred during the hypertrophic phase were dissolved.  The lab state that the parallel fibres in mice with no GluD2 receptor remained in the degenerative phase. They conclude that this indicates that GluD2 plays a pivotal role in the regenerative rewiring of parallel fibres.

The team surmise that their findings highlight that synaptic connections in the adult brain can regenerate with aid of GluD2.  For the future, the researchers state that further understanding of the role of GluD2 may allow the global medical community to unlock the regenerative capacity in the central nervous system.

Source: Hokkaido University


The number of parallel fibers (PF) was largely reduced on day 1. Parallel fibers were thickened and their terminals were enlarged on day 7. The number of parallel fibers and synapses was recovered on day 30.  Credit: (Ichikawa R. et. al., The Journal of Neuroscience, April 27, 2016).
The number of parallel fibers (PF) was largely reduced on day 1. Parallel fibers were thickened and their terminals were enlarged on day 7. The number of parallel fibers and synapses was recovered on day 30. Credit: (Ichikawa R. et. al., The Journal of Neuroscience, April 27, 2016).

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