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Metabolic Determinants of Cerebellar Circuit Formation and Maintenance

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Abstract

Cells configure their metabolism in a synchronized and timely manner to meet their energy demands throughout development and adulthood. Transitions of developmental stages are coupled to metabolic shifts, such that glycolysis is highly active during cell proliferation, whereas oxidative phosphorylation prevails in postmitotic states. In the cerebellum, metabolic transitions are remarkable given its protracted developmental timelines. Such distinctive feature, along with its high neuronal density and metabolic demands, make the cerebellum highly vulnerable to metabolic insults. Despite the expansion of metabolomic approaches to uncover biological mechanisms, little is known about the role of metabolism on cerebellar development and maintenance. To illuminate the intricate connections between metabolism, physiology, and cerebellar disorders, we examined here the impact of metabolism on cerebellar growth, maturation, and adulthood through the lens of inborn errors of metabolism.

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Funding

This work was supported by NIH grants 5K08NS110877-04 (IMV), Child Neurology Foundation (IMV), and Basil O’Connol Young Investigator Award (IMV).

Author information

Authors and Affiliations

  1. The Abimael Laboratory of Neurometabolism, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Manuel Gonzalez-Rodriguez & Isaac Marin-Valencia

  2. Departments of Neuroscience, Genetics and Genomics Medicine, and Pediatrics Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Isaac Marin-Valencia

Authors
  1. Manuel Gonzalez-Rodriguez
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  2. Isaac Marin-Valencia
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Contributions

MGR and IMV conceived the project, created and curated the database, analyzed and interpreted the data, and wrote the manuscript.

Corresponding author

Correspondence to Isaac Marin-Valencia.

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Not applicable. All data used in this study was obtained from public databases. No patient or family information has been used.

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Supplementary Information

Below is the link to the electronic supplementary material.

12311_2023_1641_MOESM1_ESM.pdf

Supplementary figure 1. Structural cerebellar phenotypes. Distributions of subgroups of IEM within each structural phenotype of the cerebellum. (PDF 1416 KB)

12311_2023_1641_MOESM2_ESM.pdf

Supplementary figure 2. Distribution of subgroups of disorders of Complex Molecule and Organelle Metabolism within the developmental cerebellar phenotype. Subgroups were distributed within the cerebellum and cerebellum+ groups. Specific structural developmental defects of the cerebellum within each subgroup were included. Given the prevalence of subgroups within the cerebellum+ group, relative frequencies of brain regions involved were shown as a heatmap panel. (PDF 576 KB)

12311_2023_1641_MOESM3_ESM.pdf

Supplementary figure 3. Distribution of subgroups of disorders of Intermediary Metabolism Energy and Complex Molecule and Organelle Metabolism within the degenerative cerebellar phenotype. Subgroups were distributed with the cerebellum and cerebellum+ groups. Relative frequencies of brain regions involved in the cerebellum + are illustrated in the heatmap. (PDF 1173 KB)

12311_2023_1641_MOESM4_ESM.pdf

Supplementary figure 4. Distribution of subgroups of disorders of Complex Molecule and Organelle Metabolism and Intermediary Metabolism Energy within the developmental and degenerative cerebellar phenotypes. Subgroups were distributed with the cerebellum and cerebellum+ groups. Specific structural developmental defects of the cerebellum within each subgroup is shown. Relative frequencies of brain regions involved are shown for the cerebellum+ group in the heatmap. (PDF 593 KB)

12311_2023_1641_MOESM5_ESM.pdf

Supplementary figure 5. Distribution of groups of IEM within the cerebellum and cerebellum+ group in other cerebellar phenotypes. Within the cerebellum and cerebellum+ groups, the presence or absence of cerebellar motor deficits, atrophy, and additional brain lesions are indicated. (PDF 18910 KB)

12311_2023_1641_MOESM6_ESM.pdf

Supplementary figure 6. Distribution of biochemical changes of other IEM groups within each cerebellar phenotype. (PDF 403 KB)

12311_2023_1641_MOESM7_ESM.pdf

Supplementary figure 7. Distribution of cerebellar structural lesions within each IEM group presenting with ataxia. (PDF 127 KB)

12311_2023_1641_MOESM8_ESM.pdf

Supplementary figure 8. Distribution of cerebellar deficits in disorders of Intermediary Metabolism Energy. (PDF 2966 KB)

12311_2023_1641_MOESM9_ESM.pdf

Supplementary figure 9. Relative frequencies of subgroups, cerebellar phenotypes, brain regions involved and type of lesions, and associated clinical deficits in other IEM groups. (PDF 492 KB)

Supplementary Table 1 (XLSX 242 KB)

Supplementary Table 2 (XLSX 7902 KB)

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Gonzalez-Rodriguez, M., Marin-Valencia, I. Metabolic Determinants of Cerebellar Circuit Formation and Maintenance. Cerebellum (2023). https://doi.org/10.1007/s12311-023-01641-2

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