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Neuronal DSCAM regulates the peri-synaptic localization of GLAST in Bergmann glia for functional synapse formation.

ABSTRACT: In the central nervous system, astrocytes enable appropriate synapse function through glutamate clearance from the synaptic cleft; however, it remains unclear how astrocytic glutamate transporters function at peri-synaptic contact. Here, we report that Down syndrome cell adhesion molecule (DSCAM) in Purkinje cells controls synapse formation and function in the developing cerebellum. Dscam-mutant mice show defects in CF synapse translocation as is observed in loss of function mutations in the astrocytic glutamate transporter GLAST expressed in Bergmann glia. These mice show impaired glutamate clearance and the delocalization of GLAST away from the cleft of parallel fibre (PF) synapse. GLAST complexes with the extracellular domain of DSCAM. Riluzole, as an activator of GLAST-mediated uptake, rescues the proximal impairment in CF synapse formation in Purkinje cell-selective Dscam-deficient mice. DSCAM is required for motor learning, but not gross motor coordination. In conclusion, the intercellular association of synaptic and astrocyte proteins is important for synapse formation and function in neural transmission.

SUBMITTER: Dewa KI

PROVIDER: S-EPMC10834496 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Neuronal DSCAM regulates the peri-synaptic localization of GLAST in Bergmann glia for functional synapse formation.

Dewa Ken-Ichi KI Arimura Nariko N Kakegawa Wataru W Itoh Masayuki M Adachi Toma T Miyashita Satoshi S Inoue Yukiko U YU Hizawa Kento K Hori Kei K Honjoya Natsumi N Yagishita Haruya H Taya Shinichiro S Miyazaki Taisuke T Usui Chika C Tatsumoto Shoji S Tsuzuki Akiko A Uetake Hirotomo H Sakai Kazuhisa K Yamakawa Kazuhiro K Sasaki Takuya T Nagai Jun J Kawaguchi Yoshiya Y Sone Masaki M Inoue Takayoshi T Go Yasuhiro Y Ichinohe Noritaka N Kaibuchi Kozo K Watanabe Masahiko M Koizumi Schuichi S Yuzaki Michisuke M Hoshino Mikio M

Nature communications 20240201 1

In the central nervous system, astrocytes enable appropriate synapse function through glutamate clearance from the synaptic cleft; however, it remains unclear how astrocytic glutamate transporters function at peri-synaptic contact. Here, we report that Down syndrome cell adhesion molecule (DSCAM) in Purkinje cells controls synapse formation and function in the developing cerebellum. Dscam-mutant mice show defects in CF synapse translocation as is observed in loss of function mutations in the ast ...[more]

PMID: 38302444

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Project description:Bergmann glia facilitate granule neuron migration during development and maintain the cerebellar organization and functional integrity. At present, molecular control of Bergmann glia specification from cerebellar radial glia is not fully understood. In this report, we show that ZEB2 (aka, SIP1 or ZFHX1B), a Mowat-Wilson syndrome-associated transcriptional regulator, is highly expressed in Bergmann glia, but hardly detectable in astrocytes in the cerebellum. The mice lacking Zeb2 in cerebellar radial glia exhibit severe deficits in Bergmann glia specification, and develop cerebellar cortical lamination dysgenesis and locomotion defects. In developing Zeb2-mutant cerebella, inward migration of granule neuron progenitors is compromised, the proliferation of glial precursors is reduced, and radial glia fail to differentiate into Bergmann glia in the Purkinje cell layer. In contrast, Zeb2 ablation in granule neuron precursors or oligodendrocyte progenitors does not affect Bergmann glia formation, despite myelination deficits caused by Zeb2 mutation in the oligodendrocyte lineage. Transcriptome profiling identified that ZEB2 regulates a set of Bergmann glia-related genes and FGF, NOTCH, and TGFβ/BMP signaling pathway components. Our data reveal that ZEB2 acts as an integral regulator of Bergmann glia formation ensuring maintenance of cerebellar integrity, suggesting that ZEB2 dysfunction in Bergmann gliogenesis might contribute to motor deficits in Mowat-Wilson syndrome.SIGNIFICANCE STATEMENT Bergmann glia are essential for proper cerebellar organization and functional circuitry, however, the molecular mechanisms that control the specification of Bergmann glia remain elusive. Here, we show that transcriptional factor ZEB2 is highly expressed in mature Bergmann glia, but not in cerebellar astrocytes. The mice lacking Zeb2 in cerebellar radial glia, but not oligodendrocyte progenitors or granular neuron progenitors, exhibit severe defects in Bergmann glia formation. The orderly radial scaffolding formed by Bergmann glial fibers critical for cerebellar lamination was not established in Zeb2 mutants, displaying motor behavior deficits. This finding demonstrates a previously unrecognized critical role for ZEB2 in Bergmann glia specification, and points to an important contribution of ZEB2 dysfunction to cerebellar motor disorders in Mowat-Wilson syndrome.

Dataset Information

Neuronal DSCAM regulates the peri-synaptic localization of GLAST in Bergmann glia for functional synapse formation.

Publications

Neuronal DSCAM regulates the peri-synaptic localization of GLAST in Bergmann glia for functional synapse formation.

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