Synaptic origins of cerebellar disease

Speaker: Roy V. Sillitoe
Department: Department of neuroscience
Subject: Synaptic origins of cerebellar disease
Location: Queridozaal (Erasmus MC)
Date: 06-06-2016

Author: Kristian Blom

At the sixth of July I visited a seminar given by Roy Sillitoe, assistant professor at the Baylor College of medicine in Houston. Roy Sillitoe’s major goal of research is to determine the biological bases underlying complex pediatric neurological diseases. He did his PhD at the university of Calgary. After that he did a short Postdoc at Oxford. During this seminar, dr. Sillitoe discussed his recent unpublished work about the synaptic origins of cerebellar diseases.

Dr. Sillitoe and his group use the cerebellum as a model system for understanding how circuits form and function. Molecular damage to the cerebellum cause different motoric problems: Tremor, ataxia and dystonia are examples of such diseases. Now the question is: How do these diseases arise from a single circuit? How does one single cell type give rise to such diverse set of diseases? It turns out that this is not quite simple from a molecular point of view.

Figure 1 – Cytoarchitecture and connectivity in the cerebellum. (A) Mouse brain shown from a lateral view with the cerebellum highlighted in color. (B) The basic cerebellar circuit is comprised of granule cells, Purkinje cells, stellate and basket cell interneurons, and deep nuclei.                                                                                                                                                                                                     (Source: Roy V Sillitoe et al. (2013) New roles for the cerebellum in health and disease. Frontiers in Systems Neuroscience 7:83.)

The disease Dr. Sillitoe focuses on is dystonia, a neurological movement disorder in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. Dystonia is the third most common cerebellum disease, behind Parkinson and tremor. Dystonia can either be inherited or acquired. In case of the former, dystonia can be broadly divided in two major categories: DYT1 early onset generalized dystonia and non-DYT1 early onset dystonia. DYT1 generalized dystonia is known to be caused by a specific mutation in the DYT1 gene.

Doing research to dystonia requires mice which you can genetically modify to express the dystonia disease. Unfortunately, when you mutate those genes in mice which are normally mutated in people with dystonia, they won’t express the dystonia phenotype at all. But if mutations of these genes doesn’t work, how do we get the disease phenotype in mice? Well, recent evidence suggests that the cerebellum is not only involved in dystonia, but it can instigate dystonia. In other words: it may not be mutations in the cerebellum itself that cause dystonia, but the signals which are transferred through the cerebellum that are the ‘inputs’ to the motor system might be at fault in this disease. So we don’t have to do anything with mutations of the cerebellum, but with the signals passing through the cerebellum. Luckily, the inferior olive, the largest nucleus situated in the lower portion of the brain stem, has a powerful and unique excitatory connection to the cerebellum. But can we use the inferior olive of the cerebellum circuitry as an inroad for designing a more flexible model for understanding dystonia? Dr. Sillitoe tackled this challenge by selectively blocking neuro-transmission to the cerebellum. His hypothesis about this experiment was: Selectively silencing developing olivo-cerebellar synapses will cause circuit malformations that induce dystonia in mice. And it turns out he was right!

After Dr. Sillitoe succeeded in showing that selectively blocking of signals to the cerebellum resulted in a dystonia phenotype, a new question came around the corner: Is a bad cerebellum signal worse than no signal at all? This question was answered by inactivating the cerebellum in mice using an osmotic pump filled with lidocaine, which is a chemical agent that can inactivate the cerebellum. An osmotic pump provide researchers with a method for controlled and continuous agent delivery in vivo. Mice which first displayed dystonia, totally lacked the dystonia phenotype after the osmotic pump was activated. Hence, this suggest that a bad cerebellum signal is indeed more worse than no signal at all.

Finally, I want to end with something I found rather cool: Deep brain stimulation (DBS). DBS is an effective therapy for neurological and neuropsychiatric diseases that uses electrodes which are inserted in the brain. Dr. Sillitoe and his group tried to recover movement by DBS of the cerebellar. And guess what… they succeeded! It turns out that DBS directed to the cerebellum significantly improves mobility. But how DBS does this is so far unknown. Perhaps that in a couple of years some nanobiologists, with their knowledge about systems and signals (which is very relevant for DBS), have the answer to this question.


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