The Cognitive Deficits of Mice and Men: How the cerebellum contributes to the cognitive symptoms of SCA1

Written by Kim M. Gruver Edited by David Bushart

What’s cognition got to do with ataxia? Could the cerebellum mediate both cognitive and motor symptoms in the same disease? And how can scientists use mice to find out?

Spinocerebellar ataxia type 1, or SCA1, is a progressive neurodegenerative disease that has no cure. In SCA1, an expanded CAG repeat sequence in the ATXN1 gene increases the chain length of the amino acid glutamine (Q), so SCA1 is called a “polyQ” disease. As suggested by its name, the cerebellum is a heavily affected brain region in SCA1. Since the cerebellum is involved in motor coordination, it is no surprise that dysregulated control of movement, or ataxia, is a major symptom of SCA1.

However, what may come as a surprise is that some SCA1 patients also experience changes in cognition in addition to ataxia. Since the mutated ATXN1 gene is found throughout the brain, it has been difficult to tease apart whether the cerebellum contributes to the cognitive symptoms of SCA1 in addition to the motor symptoms. It is possible that cognitive symptoms of SCA1 might be exclusively caused by brain regions other than the cerebellum. For example, ATXN1 is also highly expressed in the prefrontal cortex, a region known for mediating many cognitive processes. But before we discount the possibility that the cerebellum plays a role in the cognitive symptoms experienced by some SCA1 patients, it is important to note an interesting observation in neuroscience research that has emerged in recent decades. Scientists have described a surprising role of the cerebellum in a host of neurological disorders like autism and schizophrenia. In light of these findings, that the cerebellum could be implicated in both the motor and cognitive symptoms of SCA1 may not be so far-fetched.

two borwn lab mice held in the hand of a researcher wearing plastic gloves
Two lab mice from the National Institutes of Health, image courtesy of WikiMedia.

A powerful tool on the researcher’s lab bench to study diseases like SCA1 is the laboratory mouse. Since 1902, mice have played an indispensable role in disease research. Scientists can breed mice that express human genes, such as a mutated form of ATXN1, to figure out what goes awry in diseases like SCA1. Animal models of disease help researchers to identify potential treatment strategies that may be useful to humans. Since such in-depth analysis and careful experimental manipulation is impossible in human patients, animal models are an invaluable tool to study diseases like SCA1.

In the SCA1 field, scientists use multiple animal models to study SCA1. Researchers have harnessed the differences between these mouse models to address different questions, such as:

  • “How does the number of CAG repeats affect SCA1 symptoms in mice?”
  • “What happens if the ATXN1 gene is removed altogether?”
  • “Do SCA1 symptoms still occur if the mutant ATXN1 gene is restricted to cerebellar Purkinje cells?

 In mice and in humans, we know that the length of the polyQ expansion in the ATXN1 gene correlates with both the severity and the age of symptom onset of SCA1. Mice that express more CAG repeats (a longer polyQ expansion) in their ATXN1 gene experience more severe symptoms that start earlier in life than mice with a shorter polyQ expansion. When mutant ATXN1 expression is restricted to Purkinje cells in the cerebellum, mice display motor impairments similar to what is observed in mice with mutant ATXN1 expression everywhere in the brain. This tells us that disrupting healthy ATXN1 expression in Purkinje cells alone is sufficient to cause motor symptoms that stem from SCA1. To put it plainly, mouse models of SCA1 have been a crucial component of SCA1 research.

Since human SCA1 patients experience behavioral symptoms, scientists also use behavioral tools to evaluate the symptoms of SCA1 mice. Motor coordination tests are essential in ataxia research. These tests allow scientists to determine whether a potential intervention improves or worsens symptoms in mice. This is the first step to evaluate whether an intervention could be promising for human patients. However, as we discussed earlier, motor impairments are not the only symptom faced by SCA1 patients: many exhibit cognitive deficits as well. But could mice be used to evaluate something as complex as cognition? Can laboratory mice really help scientists uncover whether the cerebellum contributes to the cognitive impairments observed in SCA1? Researchers at the University of Minnesota say yes.

Continue reading “The Cognitive Deficits of Mice and Men: How the cerebellum contributes to the cognitive symptoms of SCA1”

Brain-derived neurotrophic factor: A new (old) hope for the treatment of SCA1

Written by Eviatar Fields Edited by Dr. Vitaliy Bondar

Scientists use Brain Derived Neurotrophic Factor to delay motor symptom onset and cell death in a mouse model of Spinocerebellar Ataxia Type 1

Spinocerebellar ataxia type 1 (SCA1) is a rare neurodegenerative disease that affects about 2 out of 100,000 individuals. Patients with SCA1 present with motor symptoms such as disordered walking, poor motor coordination and balance problems by their mid-thirties and will progressively get worse symptoms over the next two decades. No treatments for SCA1 exists. These motor symptoms cause a significant decrease in patient independence and quality of life. Scientists use mouse models that recreate many SCA1 symptoms to understand the cause of this disease and test new treatments.

In this paper, Mellesmoen and colleagues use a mouse model of SCA1 which presents with severe motor symptoms by adulthood. In order to measure the severity of the motor problems in the SCA1 mouse model, the researchers use a test called a rotarod. The rotarod test is similar to a rolling log balance: mice are placed on a rotating drum that slowly accelerates. Mice that can stay on the drum for longer durations have better motor coordination than mice who fall off the drum earlier. Mellesmoen was trying to find a way to get the mice to stay on the drum for longer.

artistic cartoon of male doctor sin from of a microscope and large DNA model
Cartoon of a medical researcher holding a clipboard.

Purkinje cells, the main cells of the cerebellum, eventually die in SCA1 mouse models and in patients later in life. However, it remains unclear how and why these brain cells, which are responsible for the fine-tuning of movement and motor coordination, die. This is an important question as its answer might lead to new treatments that prevent brain cells from dying which might improve SCA1 symptoms. One possibility is that some changes in gene expression (that is, how “active” or “inactive” a gene is) causes the cells to die in SCA1 mice. To test this hypothesis, the authors used a technique called RNA-seq to examine how gene expression is altered in SCA1 mice compared to healthy mice.

Continue reading “Brain-derived neurotrophic factor: A new (old) hope for the treatment of SCA1”

Snapshot: What is an ion channel?

One of the most important features of neurons (Purkinje cells, for example), is that they are capable of electrical communication. Think of the last time you saw a TV intro or movie montage with a depiction of the brain on a microscopic level – though it’s technically invisible to the naked eye, that ‘spark’ you can see traveling down a portion of the neuron is actually not too far from reality. One of the most common ways to describe an active neuron, in fact, is to say that it’s “firing.” Essentially, when a neuron is activated, it ‘fires off’ an electrical impulse that is transmitted down a long, slender extension known as the axon. The axon ends where the next neuron in the circuit begins, and when the impulse arrives at that point, it initiates a series of events that allows the signal to jump to the next cell.

cartoon of neuron delivering an electrical impulse
An electrical impulse traveling down a neuron. Photo courtesy of Wikimedia.

This electrical signal is made possible by molecular machines known as ion channels. These proteins span the cell membrane, which is the barrier between the interior and exterior of the cell. When they receive a certain signal, the channel opens, allowing ions – atoms that carry an electrical charge, such as sodium, potassium, and calcium – to pass through. There are many types of proteins that allow the transport of small molecular components, but the source of a neuron’s electrical capabilities is that its channels specifically allow ions to pass into or out of the cell. Though a single ion’s charge is quite small, the large number of ions that are exchanged when a neuron’s channels open makes for a significant electrical effect – enough to produce an electrical signal that allows neurons to communicate with one another, giving us the ability to think, move, and interact with our environment.

diagram of an ion channgel in the closed, open, and inactivated state.
Cartoon of an ion channel in different states. Photo courtesy of Wikimedia.

Though the mutations that cause SCAs typically occur in genes that are expressed in every cell of the body, disease is usually restricted to the brain. One theory about why this is the case is that these SCA-related genes are necessary for the health and maintenance of ion channels in certain brain tissues – namely, the cerebellum and brainstem. At any rate, there is evidence that the electrical activity of these brain regions is abnormal in many SCAs, which strongly suggests that ion channels play a critical role in these disorders.

If you would like to learn more about ion channels, take a look at this Encyclopaedia Britannica article.

Snapshot written by Logan Morrison edited by Dr. David Bushart

 

 

Snapshot: What are Purkinje cells?

Purkinje cells are important neuronal cells located in the outer layers of the cerebellum. The cerebellum is part of the brain that is primarily known for controlling sense of balance and movement but can also influence learning, memory, and mood.

Purkinje cells receive lots of information from other neurons through their large and highly branched processes called dendrites (Figure 1, see below). This information is processed in large oval cell bodies of Purkinje neurons and is transmitted from Purkinje neurons through their axons, another type of neuronal process, to other neurons residing deep within the cerebellum.

Left, drawing of purkinje neuron. Right, image of a tree
Figure 1. Drawing of Purkinje cell by Spanish scientist Ramon y Cajal illustrating large and beautiful dendrites (bottom of dendrite labeled with d, top labeled by arrow) and axon (labeled with a). Information flows from top to bottom in this image, where Purkinje neurons receive input in the dendrites, process it in the cell body, and transmit it to other neurons through the axon (a). Photo of tree is on the right for comparison.

Purkinje cells look a lot like trees. The dendrites are like the leaves and branches, the cell body is like the tree trunk, and the axon is like the roots. Information starts at the top and goes to the bottom. This information processing ensures balance and accuracy of movements.

Because of these important roles, dysfunction or loss of Purkinje cells often leads to problems with balance and movement. Indeed, a loss of normal Purkinje neuron function appears to be very important for the development of ataxia.

Many researchers study different inherited ataxias by expressing mutant proteins in Purkinje cells in mouse models of these diseases. For example, the first mouse model created for spinocerebellar ataxia type 1 (SCA1), called ATXN1[82Q], expresses mutant Ataxin-1 only in Purkinje neurons. These mice develop balance and movement deficits and were critical for increasing our understanding of how Purkinje neurons influence how SCA1 progresses.

If you would like to learn more about Purkinje cells, take a look at this Encyclopaedia Britannica article.

Snapshot written by Dr. Marija Cvetanovic, edited by Dr. David Bushart