Developmental Maturation of the Cerebellar White Matter—an Instructive Environment for Cerebellar Inhibitory Interneurons

Groteklaes, Anne; Bönisch, Carina; Eiberger, Britta; Christ, Andrea; Schilling, Karl

doi:10.1007/s12311-020-01111-z

Cited by 10 publications

(10 citation statements)

References 57 publications

(75 reference statements)

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“…Most of the c-Fos-positive cells had an overlap with NeuN ( Figure 1—figure supplement 2A ), but not with GAD67 ( Figure 1—figure supplement 2B ). As previously reported ( Groteklaes et al, 2020 ), clear signals of GFAP, a marker of glial cells, were not detected in the DCN, and consequently, cFos-positive cells in the DCN were GFAP negative ( Figure 1—figure supplement 2C ). These results indicate that cells in the DCN activated by RS are glutamatergic neurons.…”

Section: Resultssupporting

confidence: 84%

VTA-projecting cerebellar neurons mediate stress-dependent depression-like behaviors

Baek

Park

Kim

et al. 2022

eLife

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Although cerebellar alterations have been implicated in stress symptoms, the exact contribution of the cerebellum to stress symptoms remains to be elucidated. Here, we demonstrated the crucial role of cerebellar neurons projecting to the ventral tegmental area (VTA) in the development of chronic stress-induced behavioral alterations in mice. Chronic chemogenetic activation of inhibitory Purkinje cells in crus I suppressed c-Fos expression in the DN and an increase in immobility in the tail suspension test or forced swimming test, which were triggered by chronic stress application. The combination of adeno-associated virus-based circuit mapping and electrophysiological recording identified network connections from crus I to the VTA via the dentate nucleus (DN) of the deep cerebellar nuclei. Furthermore, chronic inhibition of specific neurons in the DN that project to the VTA prevented stressed mice from showing such depression-like behavior, whereas chronic activation of these neurons alone triggered behavioral changes that were comparable with the depression-like behaviors triggered by chronic stress application. Our results indicate that the VTA-projecting cerebellar neurons proactively regulate the development of depression-like behavior, raising the possibility that cerebellum may be an effective target for the prevention of depressive disorders in human.

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Section: Resultssupporting

confidence: 84%

VTA-projecting cerebellar neurons mediate stress-dependent depression-like behaviors

Baek

Park

Kim

et al. 2022

eLife

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“…Next, we examined the expression of known glial progenitor markers in these putative GPC populations using anti-CNP (2ʹ,3ʹ-cyclic nucleotide 3ʹ-phosphodiesterase) and anti-NG2 antibodies. CNP is expressed during OL development ( Groteklaes et al., 2020 ). In P0, CNP expression was not observed in the developing cortex ( Figure S2 A), and was weakly detected in the corpus callosum of P7 cortex ( Figure S2 B), consistent with a previous report.…”

Section: Resultsmentioning

confidence: 99%

Identification of Qk as a Glial Precursor Cell Marker that Governs the Fate Specification of Neural Stem Cells to a Glial Cell Lineage

et al. 2020

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Summary During brain development, neural stem cells (NSCs) initially produce neurons and change their fate to generate glias. While the regulation of neurogenesis is well characterized, specific markers for glial precursor cells (GPCs) and the master regulators for gliogenesis remain unidentified. Accumulating evidence suggests that RNA-binding proteins (RBPs) have significant roles in neuronal development and function, as they comprehensively regulate the expression of target genes in a cell-type-specific manner. We systematically investigated the expression profiles of 1,436 murine RBPs in the developing mouse brain and identified quaking (Qk) as a marker of the putative GPC population. Functional analysis of the NSC-specific Qk -null mutant mouse revealed the key role of Qk in astrocyte and oligodendrocyte generation and differentiation from NSCs. Mechanistically, Qk upregulates gliogenic genes via quaking response elements in their 3′ untranslated regions. These results provide crucial directions for identifying GPCs and deciphering the regulatory mechanisms of gliogenesis from NSCs.

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“…Supporting our qPCR data, immunohistochemical analysis of Pax2-labelled cerebellar sections revealed that Tsc1 +/cerebella presented with an increased number Pax2 + cells (Figure 4B, C). In addition, these cells were most abundant in the cerebellar white matter (Figure 4B), altogether suggesting the presence of an immature Pax2 phenotype in Tsc1 +/mice (52,53).…”

Section: Overactive Mtor Pathway In P7 Cerebellum Leads To Perturbed Interneuron Development In Tsc1 +/Micementioning

confidence: 93%

Tsc1 haploinsufficiency leads to Pax2 dysregulation in the developing murine cerebellum

Serra

Stravs

Osório

et al. 2021

Preprint

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Tuberous sclerosis complex 1 (TSC1) is a tumour suppressor gene that inhibits the mechanistic target of rapamycin (mTOR) pathway. Mutations in TSC1 lead to a rare complex disorder of the same name, in which up to 50% of patients present with autism spectrum disorder (ASD). ASD is a highly prevalent, early-onset neurodevelopmental disorder, characterized by social deficits and repetitive behaviours, although the type and severity of symptoms show wide variability across individuals. Amongst different brain areas proposed to play a role in the development of ASD, the cerebellum is commonly reported to be altered, and cerebellar-specific deletion of Tsc1 in mice is sufficient to induce an ASD-like phenotype. Given that the mTOR pathway is crucial for proper cell replication and migration, this suggests that dysregulation of this pathway, particularly during critical phases of cerebellar development, could contribute to the establishment of ASD. Here, we used a mouse model of TSC to investigate gene and protein expression during embryonic and early postnatal periods of cerebellar development. We found that, at E18 and P7, mRNA levels of the cerebellar inhibitory interneuron marker Pax2 were dysregulated. This was accompanied by changes in the expression of mTOR pathway-related genes and downstream phosphorylation of S6. Differential gene correlation analysis revealed dynamic changes in correlated gene pairs across development, with an overall loss of correlation between mTOR- and cerebellar-related genes in Tsc1 mutants compared to controls. We corroborated the genetic findings by characterizing the mTOR pathway and cerebellar development on protein and cellular levels with Western blot and immunohistochemistry. We found that Pax2-expressing cells were hypertrophic at E18 while, at P7, their number was increased and maturation into parvalbumin-expressing cells delayed. Our findings indicate that E18 and P7 are crucial time points in cerebellar development in mice that are particularly susceptible to mTOR pathway dysregulation.

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Developmental Maturation of the Cerebellar White Matter—an Instructive Environment for Cerebellar Inhibitory Interneurons

Cited by 10 publications

References 57 publications

VTA-projecting cerebellar neurons mediate stress-dependent depression-like behaviors

VTA-projecting cerebellar neurons mediate stress-dependent depression-like behaviors

Identification of Qk as a Glial Precursor Cell Marker that Governs the Fate Specification of Neural Stem Cells to a Glial Cell Lineage

Tsc1 haploinsufficiency leads to Pax2 dysregulation in the developing murine cerebellum

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