Synaptic Origins of Cerebellar disease

Speaker: Roy Sillitoe
Department: Jan and Duncan Neurological Institute, Baylor College of Medicine
Subject: Synaptic Origins of Cerebellar disease
Location: Erasmus MC

Date: 6 June 2016
Author: Gabriele Kockelkoren

In the spirit of sharing unpublished work, Roy Sillitoe shares his knowledge on the cerebellum synapses. One of the models he is intrigued is, is how in the cerebellum it is all wired up. What are the electro physical consequences of this wiring and what happens when the wiring is not according to plan? Cerebellar damage causes serious consequences during development, which turn out to be catastrophic. Roy Sillitoe looks into these cellular and circuit consequences. How does this relatively simple circuit give rise to such great variety of diseases? From a molecular perspective, it is not as easy as it may look like, as the cerebellum is wired into highly complex topographic circuits that control behaviour.

The cerebellum is a region in the brain, which is involved in coordination, fine-tuning and motor learning. An important cell type and the most dominant one in the cerebellum, are Purkinje cells. These neurons have parallel and climbing fibers through which they receive input. The inferior olive provides the cells with input. Purkinje cells have two types of action potentials: single and complex. In this way the Purkinje cells provide feedback for motor coordination.

Over the years, his group has been intrigued in the effects within topographic zones and effects on the cerebellar circuits, when confronted to damage. To understand these connections how these connections develop, they use mouse models. In the lab they try to target the synapses.

In the time Roy Sillitoe has worked in Oxford, he tried to understand the human genetic disease Dystonia. Patients with Dystonia present involuntary sustained muscle co-contractions. This disease can be inherited or acquired. In Oxford he studied the effect of mutated proteins. These proteins incorrectly move throughout the cell, which is seen as the most probable outcome for the disease. Most of the mouse models that are based on the human genetic studies, do not display dystonic postures. However, mouse models were very informative to his group, as Sillitoe and colleagues used a mouse who displays Dystonia. Connectivity between circuits was severely reduced in mice which had Dystonia. So the conclusion could be drawn that there was something wrong at the circuit level. Recent evidence suggests that the cerebellum is not only involved in Dystonia, but it can instigate Dystonia as well.

cerebellum

Figure 1:The inferior olive inputs sensory information to the cerebellum. The Purkinje cells communicate the output. Source: http://www.neuronbank.org/wiki/index.php/Inferior_Olivary_Neurons

Sillitoe and his colleagues have been wondering whether the disease is caused by errors in the input signals. However, trying to manipulate cerebellar connections is not a trivial task. The inferior olive has a powerful and unique excitatory connection to the cerebellum. This excitation can be tracked by measuring activity of the inferior olive. This activity results in spikes of potential. Sillitoe wants to answer the question: Can we use the inferior olive to cerebellum circuitry as in inroad for designing a more flexible model for understanding dystonia? The goal is to generate a mouse model that exhibits Dystonia and understand what is happening in such mice.

They started with the hypothesis that selectively silencing developing olivo-cerebellar synapses will cause circuit malformations that induce Dystonia in mice. However, cutting the olive is not possible, as this would be catastrophic for the development of the mouse. It is however difficult to target the inferior olive because its gene expression pattern overlaps with connected regions. Therefore they have been working with the genes Ptf1a and Vglut2, which are heavily expressed in inferior olive and cerebellum. This way they made use of an unique intersection of gene expression in the inferior olive. This caused the inferior olivary neurons to release empty vesicles and thus no response is triggered. This created mice exhibiting symptoms of Dystonia. The mice were studied using electromyography (EMG), measuring local field potential (LFP) and single-unit recordings.

As a way to cure the disease, the Sillitoe lab has been looking at DBS (Deep brain stimulation) and saw that for a short period of time, the mouse regained normal movement. However, as soon as the effect stopped, the mouse showed Dystonia symptoms all over again.

This presentation was quite difficult to understand, as it contained many medical terms that are supposed to be known to the public. It is of course nice to be able to recognize and understanding gene editing machinery, however that is a very small part of a great and complex research field.

 

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