How Competition for Connectivity Shapes the Cerebellum

Competition drives neurons in the cerebellum to grow faster and branch out.

Posted Mar 12, 2021 |

  • Neurons in the cerebellum, called Purkinje cells, play a role in coordinating movement.
  • Research in mice suggests that Purkinje cells compete with one another. Beating out fellow cells leads to faster growth and more connections within the brain.
  • The gene GluD2 may facilitate this process.
Instituto Santiago Ramón y Cajal/Public Domain
Drawing of Purkinje cells (A) from pigeon cerebellum by Santiago Ramón y Cajal circa 1899.
Source: Instituto Santiago Ramón y Cajal/Public Domain

In the world of sports, competition facilitates peak performance by fortifying an athlete's motivation and determination to be "better, stronger, and faster" than his or her rivals. New research from Stanford University suggests that competitive interactions also push Purkinje cells in the cerebellum to grow faster and make more synaptic connections than their rivals. These findings (Takeo et al., 2021) appear in the February 17 issue of Neuron.

Purkinje cells are the only neurons that have outward projections from the cerebellar cortex. Hence, these uniquely shaped neurons play a pivotal role in coordinating movements necessary for everyday activities (e.g., riding a bike, driving a stick shift, touch typing, etc.) that become automatic with practice.

The structure and functional connectivity of Purkinje cells is also key to athletic prowess and well-conditioned muscle memory in sports. Having healthy Purkinje cells with robust connectivity to other brain regions facilitates fluid performance, whereas dysfunction of the cerebellum's Purkinje cells is associated with movement problems and ataxia. (Miterko et al., 2021)

From a metacognitive perspective, the recent discovery that competition among Purkinje cells helps them flourish mirrors the role that these tree-shaped neurons play in helping athletes triumph over their competitors by moving with perfectly-timed precision, fluidity, and grace. (See "Newfound Benefits of Stimulating the Cerebellum at 13 Hz.")

The latest cerebellum findings shed light on how neural circuits form and how the cerebellum and other brain regions get wired together via neuroplasticity. Liqun Luo is this study's senior author; co-first authors Yukari Takeo and S. Andrew Shuster contributed equally to the research.

"Purkinje cells are my first love because they were the first mammalian neurons I studied, while I was still a postdoc," Luo said in a March 11 news release. "They look like beautiful trees and there are many genetic tools to study them." According to Luo, this study addresses some "big unanswered questions" such as "How does the brain get wired up?" and "How do neural circuits form?"

"Imagine one Purkinje cell is a tree," he added. "Labeling individual cells allows you to light up one whole tree in a dense forest of neurons, whereas if all Purkinje cells are labeled, it is difficult to visualize how an individual tree looks."

How Mice Revealed Neural Functioning

For this first-of-its-kind study, Luo and his lab members used genetically engineered knockout mice who lacked the GluD2 gene and compared how their Purkinje cells functioned during a side-by-side comparison to non-knockout mice with the GluD2 gene. The researchers also used computer models to simulate dendrite growth and early synapse formation.

Luo and his coauthors found that the dendrite branches of Purkinje cells seem to compete with one another in a "winner take all" type of competition to grow faster and beat their challengers in a race to form early synaptic connections. Trailblazing Purkinje cells that make successful connections right out of the gate seem to experience an upward spiral that exponentially boosts that particular neurons' odds of experiencing faster dendritic growth and subsequently making more and more synaptic connections.

Notably, the researchers found that mice without the GluD2 gene were handicapped when it came to growing quickly and making early synaptic connections. Purkinje cells lacking this gene had very slow dendrite growth early on, which resulted in dendrite morphogenesis that made their shape not like trees but rather like "upside-down pyramids."

Conversely, Purkinje cells with the GluD2 gene thrived. As the authors explain: "Purkinje cells with the functioning GluD2 gene grew in their usual boxy shape with even dendrite branches at the tree's bottom (early growth) and top (later growth)."

"The key to this study is the ability to compare neighboring Purkinje cells that have and lack the GluD2 gene," Luo noted. "This reveals the competition among dendrites for synapses and how dendrites grow with normal or reduced synapses to stabilize them."

"Our results support the synaptotrophic hypothesis at initial stages of dendrite development, suggest a second mode in which cumulative synapse formation inhibits further dendrite growth, and highlight the importance of competition in dendrite morphogenesis," the researchers conclude.

References

Yukari H. Takeo, S. Andrew Shuster, Linnie Jiang, Miley C. Hu, David J. Luginbuhl, Thomas Rülicke, Ximena Contreras, Simon Hippenmeyer, Mark J. Wagner, Surya Ganguli, Liqun Luo. "GluD2- and Cbln1-Mediated Competitive Interactions Shape the Dendritic Arbors of Cerebellar Purkinje Cells." Neuron (Published: February 17, 2021) DOI: 10.1016/j.neuron.2020.11.028

Lauren N. Miterko, Tao Lin, Joy Zhou, Meike E. van der Heijden, Jaclyn Beckinghausen, Joshua J. White & Roy V. Sillitoe. "Neuromodulation of the Cerebellum Rescues Movement in a Mouse Model of Ataxia." Nature Communications (First published: February 26, 2021) DOI: 10.1038/s41467-021-21417-8