Inputs from Sequentially Developed Parallel Fibers Are Required for Cerebellar Organization

Park, Heeyoun; Kim, Tae-Gon; Kim, Jinhyun; Yamamoto, Yukio; Tanaka-Yamamoto, Keiko

doi:10.1016/j.celrep.2019.08.010

Cited by 18 publications

(19 citation statements)

References 75 publications

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“…Of note, agenesis of the cerebellar vermis has been described in individuals with CHD8 (p.Cys1691Tyr) mutations (Firth et al, 2009; DECI-PHER 259269), suggesting that CHD8 deficiency results in abnormal development of the cerebellum not only in mice but also in humans. Given that synaptic transmission from PFs of CGNs to Purkinje cells has been shown to be highly related to motor function (Kashiwabuchi et al, 1995;Hirai et al, 2005;Kakegawa et al, 2009;Park et al, 2019), it is possible that the motor dysfunction apparent in Atoh1-Cre/Chd8 L F/F mice is attributable to disruption of cerebellar circuits caused by the reduced number and altered synaptic function of CGNs. Our ChIP-seq data for CHD8 in GNPs showed that CHD8 was bound to the promoter regions of many synapse-related genes, including Slc17a7, and thereby directly regulates the expression of these target genes.…”

Section: Discussionmentioning

confidence: 99%

The autism-associated protein CHD8 is required for cerebellar development and motor function

et al. 2021

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Section: Discussionmentioning

confidence: 99%

The autism-associated protein CHD8 is required for cerebellar development and motor function

et al. 2021

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“…The severity of motor impairments and electrophysiological changes in Purkinje cells in our agranular mice was surprising, given that silencing granule cell synapses results in minor changes in Purkinje cell firing (Galliano et al, 2013). Furthermore, in multiple models, impairing parallel fiber synapses results in motor impairments that can be assessed with the rotor rod assay (Aiba et al, 1994;Park et al, 2019), which we could not do due to the severity of motor impairment in En1 Cre/+ ;Atoh1 fl/mice. Taking these results together, from a technical standpoint, when one seeks to resolve developmental mechanisms, we must not only consider what is manipulated, but also how it is manipulated.…”

Section: Discussionmentioning

confidence: 80%

“…We also examined the morphology of P14 Purkinje cells since previous studies suggest that decreased excitatory input alters Purkinje cell dendrite outgrowth (Bradley and Berry, 1976;Park et al, 2019). Using Golgi-Cox staining, we found that Purkinje cells in En1 Cre/+ ;Atoh1 fl/mice had stunted and smaller dendritic arbors compared to controls (Figure 2F).…”

Section: Purkinje Cells In En1mentioning

confidence: 96%

Maturation of Purkinje cell firing properties relies on granule cell neurogenesis

Heijden

Lackey

Işleyen

et al. 2020

Preprint

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37Preterm infants that suffer cerebellar insults often develop motor disorders and cognitive 38 difficulty. Granule cells are especially vulnerable, and they likely instigate disease by impairing 39 the function of Purkinje cells. Here, we use regional genetic manipulations and in vivo 40 electrophysiology to test whether granule cells help establish the firing properties of Purkinje 41 cells during postnatal mouse development. We generated mice that lack granule cell 42 neurogenesis and tracked the structural and functional consequences on Purkinje cells in these 43 agranular pups. We reveal that Purkinje cells fail to acquire their typical connectivity and 44 morphology, and the formation of characteristic Purkinje cell firing patterns is delayed by one 45 week. We also show that the agranular pups have impaired motor behaviors and vocal skills. 46 These data argue that granule cell neurogenesis sets the maturation time window for Purkinje cell 47 51 Abnormal cerebellar development instigates motor diseases and neurodevelopmental disorders 52 including ataxia, dystonia, tremor, and autism. These conditions are highly prevalent in 53 premature infants and in newborns with cerebellar hemorrhage (Dijkshoorn et al., 2020; 54 Limperopoulos et al., 2007; Steggerda et al., 2009; Zayek et al., 2012), who ultimately attain a 55 smaller cerebellar size compared to children born full-term (Limperopoulos et al., 2005; Volpe, 56 2009). During the third trimester of human development, which corresponds to the first two 57 postnatal weeks in mice (Sathyanesan et al., 2019), the cerebellum increases five-fold in size due 58 to the rapid proliferation of granule cell precursors and the integration of granule cells into the 59 cerebellar circuit (Chang et al., 2000). Observations from clinical data indicate a strong 60 correlation between cerebellar size and cognitive disorders, suggesting that this period of 61 cerebellar expansion is a critical developmental time-window for establishing cerebellar 62 function. Pig and mouse studies confirm that preterm birth, postnatal hemorrhage and hypoxia all 63 result in lower granule cell numbers (Iskusnykh et al., 2018; Yoo et al., 2014) and abnormal 64 motor control (Sathyanesan et al., 2018; Yoo et al., 2014). Importantly, such peri-and postnatal 65 insults are accompanied by impairments in the intrinsic firing properties of Purkinje cells 66 (Sathyanesan et al., 2018). Purkinje cells are the sole output of the cerebellar cortex and integrate 67 input from up to two hundred fifty thousand excitatory granule cell synapses (Huang et al., 68 2014), though the predominant Purkinje cell action potential called the simple spike, is 69 intrinsically generated (Raman and Bean, 1999). In this context, it is intriguing that genetically 70 silencing granule cells caused modest alterations to the baseline firing properties of Purkinje 71 cells and impaired only the finer aspects of motor learning, but not gross motor control (Galliano 72 et al., 2013). The discordance between the p...

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“…Mosaic analysis with double markers (MDAM) can reveal the individual morphology of developing CGNs but it requires specific lines and complex genetic crosses ( Zong et al, 2005 ). Viral vectors have been used to express fluorescent proteins in developing CGNs but the delay between the infection and the transgene expression does not allow to observe the early phases of CGN development in the EGL ( Park et al, 2019 ). The size of the transgene is also limited.…”

Section: Discussionmentioning

confidence: 99%

Plexin-B2 controls the timing of differentiation and the motility of cerebellar granule neurons

Battum

Heitz-Marchaland

Zagar

et al. 2021

eLife

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Plexin-B2 deletion leads to aberrant lamination of cerebellar granule neurons (CGNs) and Purkinje cells. Although in the cerebellum Plexin-B2 is only expressed by proliferating CGN precursors in the outer external granule layer (oEGL), its function in CGN development is still elusive. Here, we used 3D imaging, in vivo electroporation and live-imaging techniques to study CGN development in novel cerebellum-specific Plxnb2 conditional knockout mice. We show that proliferating CGNs in Plxnb2 mutants not only escape the oEGL and mix with newborn postmitotic CGNs. Furthermore, motility of mitotic precursors and early postmitotic CGNs is altered. Together, this leads to the formation of ectopic patches of CGNs at the cerebellar surface and an intermingling of normally time-stamped parallel fibers in the molecular layer (ML), and aberrant arborization of Purkinje cell dendrites. There results suggest that Plexin-B2 restricts CGN motility and might have a function in cytokinesis.

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Inputs from Sequentially Developed Parallel Fibers Are Required for Cerebellar Organization

Cited by 18 publications

References 75 publications

The autism-associated protein CHD8 is required for cerebellar development and motor function

The autism-associated protein CHD8 is required for cerebellar development and motor function

Maturation of Purkinje cell firing properties relies on granule cell neurogenesis

Plexin-B2 controls the timing of differentiation and the motility of cerebellar granule neurons

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