Gait and motor performance is affected in many neurological diseases. Ataxia is a common problem in Parkinson’s disease (PD), and a large part of early onset Alzheimer’s disease patients (AD) also deal with it. Motor skills can also affected in patients autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD).
The cerebellum plays a crucial role in motor coordination, precision, and accurate timing and thus is of interest in many studies in this area. However, testing specifically for cerebellar functioning has always been difficult and invasive. A couple of years ago, the Erasmus MC (Rotterdam, The Netherlands) started the development of the ErasmusLadder, a complete testing apparatus, specially designed to test the cerebellum.
The ErasmusLadder is an instrument for testing motor learning. It consists of a horizontal ladder stretching between two goal boxes, with rungs for the animal to walk on; some are “higher” and some are “lower”. A ‘correct’ stepping pattern involves using the higher rungs; using a lower rung is counted as a misstep. Sensors detect when the mouse steps on a rung, so step time, step size, missteps and other parameters can be measured. While similar methods focus on either spatial patterns, general aspects of locomotion, or on balance, ErasmusLadder combines these features in one test.
Jan-Willem Potters studied the role of the cerebellum in different aspects of behavior, ranging from simple reflex-like movements to complex systems such as emotion and cognition, and wrote about it in this blog post. In his research group, they studied specific mutations of plasticity and how they affected the cerebellum. During that time, they were also developing the ErasmusLadder.
Detailed parameters of locomotion
In this publication, results from an ErasmusLadder test with mice that lack specific proteins that play a role in the structure or the formation of new memories in the cerebellum were published. This paper clearly shows how specific mutations affect locomotion.
Practical advantages of ErasmusLadder
According to Potters, working with the ErasmusLadder has several advantages. The experiments take relatively little time with 15-20 minutes per session, and the apparatus works fully automatically. This makes it possible to easily study mice mutants, collect data about locomotion, and quickly select candidates for further investigation. Now investigators can study extremely detailed parameters regarding locomotion, interlimb coordination and locomotor adaptation. Read more here.
The essential role of granule cells in motor learning
Cerebellar granule cells form a large and important part of the vertebrate central nervous system. To uncover the role of these neurons in motor functioning, Galliano et al. minimized the output of these cells in a mice model and compared their locomotor performance to a wild type group. The ErasmusLadder test was one of the tests used to investigate both motor performance and motor learning skills. Interestingly, they found that overall motor performance was intact, indicating that only a few functioning granule cells are necessary for this.
Galliano, E.; Gao, Z.; Schonewille, M.; Todorov, B.; Simons, E.; Pop, A.S.; D’Angelo, E.; Maagenberg, A.M.J.M.; Hoebeek, F.E.; De Zeeuw, C. (2013). Silencing the Majority of Cerebellar Granule Cells Uncovers Their Essential Role in Motor Learning and Consolidation. Cell Reports, 3, 1239-1251.
Different cells have different roles in motor performance
Maria Fernanda Vinueza Veloz and her colleagues also investigated specific neurons. In their study Purkinje cells, interneurons, and granule cells where the focus. Several knock-out strains were tested on the EramusLadder to unravel the role of each of the cell types. Motor performance was decreased in mice with decreased Purkinje cell output, as was evident from their ataxia-like phenotype. Other knock-out strains did not seem impaired in their motor performance, however, motor learning was difficult for all the treated mice. In addition, none of the mice showed lack of motivation as was evident from their willingness to leave the goal box. (For more about this research see this blog post.)
Vinueza Veloz, M.F.; Zhou, K.; Bosman, L.W.J.; Potters, J.-W.; Negrello, M.; Seepers, R.M.; Strydis, C.; Koekkoek, S.K.E.; De Zeeuw, C.I. (2014). Cerebellar control of gait and interlimb coordination. Brain Structure and Function, doi: 10.1007/s00429-014-0870-1.
Do plaques in the cerebellum cause ataxia?
Diego Sepulveda-Falla and his colleagues were part of a study that was described in the media as groundbreaking research. They worked together with a cohort of 25 families from the Antioquia area in Colombia with a high prevalence of early onset familial Alzheimer’s (FAD) that was discovered to be caused by a mutation in the presenile1 (PS1) gene. Here, patients were symptomatic even before beta amyloid plaques were likely to occur in the brain, which is striking, since these protein build-ups in the brain were main suspects in the cause of the symptoms thus far. The same effect was found in a murine model of PS1 FAD – tests with the ErasmusLadder revealed motor performance and motor learning problems even before plaques were found in the cerebellum. While previously it was thought that the gene mutation causes plaques, which in turn causes the symptoms, this study suggests that the PS1 mutation causes ataxia in these patients through a different mechanism in the cerebellum. This is especially interesting in light of the current clinical study family members have entered, because here a drug is tested that is specifically targeted at preventing the formation of plaques. The researchers are now eagerly awaiting the data to see if the ataxia also disappears (For more about this research see this blog post.)
Sepulveda-Falla, D.; Barrera-Ocampo, A.; Hagel, C.; Korwitz, A.; Vinueza-Veloz, M.F.; Zhou, K.; Schonewille, M.; Zhou, H.; Velazquez-Perez, L.; Rodriguez-Labrada, R.; Villegas, A.; Ferrer, I.; Lopera, F.; Langer, T.; De Zeeuw, C.I.; Glatzel, M. (2014). Familial Alzheimer's disease-associated presenilin-1 alter cerebellar activity and calcium homeostasis. The Journal of Clinical Investigation, 124(4), 1552-1567.