Cerebellar output neurons can impair non-motor behaviors by altering development of extracerebellar connectivity

Andrew S. Lee, Tanzil M. Arefin, Alina Gubanova, Daniel N. Stephen, Yu Liu, Zhimin Lao, Anjana Krishnamurthy, Natalia V. De Marco García, Detlef H. Heck, Jiangyang Zhang, Anjali M. Rajadhyaksha and Alexandra L. Joyner ()
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Andrew S. Lee: Sloan Kettering Institute
Tanzil M. Arefin: New York University Grossman School of Medicine
Alina Gubanova: Sloan Kettering Institute
Daniel N. Stephen: Sloan Kettering Institute
Yu Liu: University of Minnesota Medical School
Zhimin Lao: Sloan Kettering Institute
Anjana Krishnamurthy: Sloan Kettering Institute
Natalia V. De Marco García: Weill Cornell Graduate School of Medical Sciences
Detlef H. Heck: University of Minnesota Medical School
Jiangyang Zhang: New York University Grossman School of Medicine
Anjali M. Rajadhyaksha: Weill Cornell Graduate School of Medical Sciences
Alexandra L. Joyner: Sloan Kettering Institute

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract The capacity of the brain to compensate for insults during development depends on the type of cell loss, whereas the consequences of genetic mutations in the same neurons are difficult to predict. We reveal powerful compensation from outside the mouse cerebellum when the excitatory cerebellar output neurons are ablated embryonically and demonstrate that the main requirement for these neurons is for motor coordination and not basic learning and social behaviors. In contrast, loss of the homeobox transcription factors Engrailed1/2 (EN1/2) in the cerebellar excitatory lineage leads to additional deficits in adult learning and spatial working memory, despite half of the excitatory output neurons being intact. Diffusion MRI indicates increased thalamo-cortico-striatal connectivity in En1/2 mutants, showing that the remaining excitatory neurons lacking En1/2 exert adverse effects on extracerebellar circuits regulating motor learning and select non-motor behaviors. Thus, an absence of cerebellar output neurons is less disruptive than having cerebellar genetic mutations.

Date: 2025
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DOI: 10.1038/s41467-025-57080-6

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