Metabolic Determinants of Cerebellar Circuit Formation and Maintenance

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.

Keywords: Ataxia; Cerebellum; Inborn errors of metabolism; Metabolism; Neurodegeneration; Neurodevelopment.

Fig. 1

Inborn errors of metabolism with cerebellar involvement. a Distribution of groups of inborn errors of metabolism (IEM hereafter) based on absolute frequencies. b Fraction of IEM with cerebellar involvement and group distribution based on their relative frequencies. c Systemic manifestations of IEM with cerebellar involvement. d Relative frequencies of cerebellar involvement in subgroups of IEM. e Map of the metabolic network associated with cerebellar disease weighted on relative frequencies shown on panel b. Thickness and opacity of lines are proportional to relative frequencies

Fig. 2

Phenotypes of cerebellar disease in IEM. a Absolute frequencies of IEM grouped by major phenotypes: development, degeneration, development and degeneration, and others. b Relative frequencies of subgroups of IEM presenting with developmental, degenerative, developmental and degenerative, and other cerebellar phenotypes. c Types of developmental defects and their association with degeneration in each group of IEM

Fig. 3

Categorization of IEM into two groups based on their impact on the cerebellum and other brain regions. a We grouped IEM into those that primarily affect the cerebellum, referred to as the “cerebellum” group, and those that affect the cerebellum and other parts of the brain simultaneously, denoted as the “cerebellum + “ group. b Distribution of cerebellar phenotypes within the cerebellum and cerebellum + groups for each major group of IEM. c) Fold change, denoted as (cerebellum – cerebellum +)/cerebellum +, for each phenotype within each IEM group present in both the cerebellum and cerebellum + groups

Fig. 4

Biochemical parameters and common tissues involved in IEM affecting the cerebellum. Relative frequencies of the top three biochemical parameters and tissues and organs involved in the three most common IEM with cerebellar involvement across the most common cerebellar phenotypes. The group “other tests” included biochemical parameters not present in other biochemical groups such as ammonia, urea, phosphate, or sulfatides. The group “other lipids” included lipids not present in the group of fatty acids, very long chain fatty acids, or ketone bodies. N: newborn, A: adults

Fig. 5

Clinical cerebellar phenotypes in IEM with cerebellar involvement. a Distribution of clinical cerebellar deficits based on their relative frequencies. b Distribution of relative frequencies of ataxia in IEM groups and its frequency across ages in each IEM group. c Correlation analysis of the frequency of ataxia in cerebellum and cerebellum + group within each IEM. d Cerebellar structural defects associated in IEM presenting with ataxia. e Distribution of brain areas involved and lesion types in the cerebellum + group for each IEM

Fig. 6

Cerebellar deficits in disorders of complex molecule and organelle metabolism. a Relative frequencies of subgroups and cerebellar phenotypes. b Relative frequencies of clinical cerebellar phenotypes in the group and subgroups. Frequency of ataxia across ages is displayed in each subgroup. c Distribution of relative frequencies of cerebellar phenotypes in subgroups and tertiary groups. d Qualitative display of brain areas involved and type lesions in each subgroup in both developmental and degenerative phenotypes. Corp. call: corpus callosum, Basal g.: basal ganglia

Fig. 7

Cerebellar phenotype in disorders of intermediary metabolism energy. a Relative frequencies of subgroups and of cerebellar phenotypes. b Distribution of relative frequencies of structural cerebellar phenotypes in subgroups and tertiary groups. c Relative frequencies of brain areas involved in each subgroup and distribution of lesions in each brain area