Cerebellar Development and Circuit Maturation: A Common Framework for Spinocerebellar Ataxias

Binda, Francesca; Pernaci, Carla; Saxena, Smita

doi:10.3389/fnins.2020.00293

Cited by 9 publications

(6 citation statements)

References 161 publications

(180 reference statements)

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“… 2 PCs are the most vulnerable neurons in the cerebellum, and their prominent loss is the main feature in the late phase of cerebellar neurodegenerative diseases. 3 Inhibited or damaged PCs have been reported to cause a wide-based unsteady gait, extremity trajectory errors and poor accuracy performances in both animal models and human patients. 4 , 5 Nevertheless, it must be noted that although related evidence demonstrates that PCs play a key role in motor coordination, the neural circuit mechanism by which PCs precisely regulate motor coordination remains unclarified.…”

Section: Introductionmentioning

confidence: 99%

BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination

Liu

Chen

Zheng

et al. 2022

Sig Transduct Target Ther

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Cerebellar ataxias are characterized by a progressive decline in motor coordination, but the specific output circuits and underlying pathological mechanism remain poorly understood. Through cell-type-specific manipulations, we discovered a novel GABAergic Purkinje cell (PC) circuit in the cerebellar IV/V lobe that projected to CaMKIIα+ neurons in the fastigial nucleus (FN), which regulated sensorimotor coordination. Furthermore, transcriptomics profiling analysis revealed various cerebellar neuronal identities, and we validated that biorientation defective 1 (BOD1) played an important role in the circuit of IV/V lobe to FN. BOD1 deficit in PCs of IV/V lobe attenuated the excitability and spine density of PCs, accompany with ataxia behaviors. Instead, BOD1 enrichment in PCs of IV/V lobe reversed the hyperexcitability of CaMKIIα+ neurons in the FN and ameliorated ataxia behaviors in L7-Cre; BOD1f/f mice. Together, these findings further suggest that specific regulation of the cerebellar IV/V lobePCs → FNCaMKIIα+ circuit might provide neuromodulatory targets for the treatment of ataxia behaviors.

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Section: Introductionmentioning

confidence: 99%

BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination

Liu

Chen

Zheng

et al. 2022

Sig Transduct Target Ther

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“…This study also showed that, although cerebellar iTBS did not induce a significant change on serum BDNF when considering the whole group, segregating for genotype serum BDNF increased in Val66Val and decreased in Val66Met patients. BDNF is recognized as a major player in the long-term effect of rTMS [ 30 ] and has been involved in the pathogenesis of SCAs [ 44 ] and several degenerative disorders [ 19 , 20 ]; thus, changes in serum BDNF have been considered a candidate biomarker of efficacy. Despite this evidence, BDNF serum levels are differently modulated by rTMS protocol in healthy individuals and different neurological disorders.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Use of Cerebellar Intermittent Theta Burst Stimulation (iTBS) in a Sardinian Family Affected by Spinocerebellar Ataxia 38 (SCA 38)

et al. 2021

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Spinocerebellar ataxia 38 (SCA 38) is an autosomal dominant disorder caused by conventional mutations in the ELOVL5 gene which encodes an enzyme involved in the synthesis of very long fatty acids, with a specific expression in cerebellar Purkinje cells. Three Italian families carrying the mutation, one of which is of Sardinian descent, have been identified and characterized. One session of cerebellar intermittent theta burst stimulation (iTBS) was applied to 6 affected members of the Sardinian family to probe motor cortex excitability measured by motor-evoked potentials (MEPs). Afterwards, patients were exposed to ten sessions of cerebellar real and sham iTBS in a cross-over study and clinical symptoms were evaluated before and after treatment by Modified International Cooperative Ataxia Rating Scale (MICARS). Moreover, serum BDNF levels were evaluated before and after real and sham cerebellar iTBS and the role of BDNF Val66Met polymorphism in influencing iTBS effect was explored. Present data show that one session of cerebellar iTBS was able to increase MEPs in all tested patients, suggesting an enhancement of the cerebello-thalamo-cortical pathway in SCA 38. MICARS scores were reduced after ten sessions of real cerebellar iTBS showing an improvement in clinical symptoms. Finally, although serum BDNF levels were not affected by cerebellar iTBS when considering all samples, segregating for genotype a difference was found between Val66Val and Val66Met carriers. These preliminary data suggest a potential therapeutic use of cerebellar iTBS in improving motor symptoms of SCA38.

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“…The Golgi cells, which are GABAergic inhibitory interneurons, connect to the granule cells via inhibitory synapses. Additionally, they receive excitatory synaptic inputs from the mossy fibers that form the cerebellar glomerular synapses [ 1 , 2 , 21 , 22 , 26 , 27 ]. The deep cerebellar nuclei, which project to various areas of the brain, are the output structures of the cerebellum.…”

Section: Cerebellum-like Dorsal Cochlear Nucleus (Dcn) and Cerebellummentioning

confidence: 99%

“…The deep cerebellar nuclei, which project to various areas of the brain, are the output structures of the cerebellum. They can also block this signal at the subcortical level by sending a feedback projection to the inferior olive [ 1 , 2 , 21 , 22 , 25 , 26 , 27 ].…”

Section: Cerebellum-like Dorsal Cochlear Nucleus (Dcn) and Cerebellummentioning

confidence: 99%

Focusing on the Emerging Role of Kainate Receptors in the Dorsal Cochlear Nucleus (DCN) and Cerebellum

Tang²

2023

IJMS

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Mammals have a dorsal cochlear nucleus (DCN), which is thought to be a cerebellum-like structure with similar features in terms of structure and microcircuitry to the cerebellum. Both the DCN and cerebellum perform their functions depending on synaptic and neuronal networks mediated by various glutamate receptors. Kainate receptors (KARs) are one class of the glutamate receptor family and are strongly expressed in the hippocampus, the cerebellum, and cerebellum-like structures. The cellular distribution and the potential role of KARs in the hippocampus have been extensively investigated. However, the cellular distribution and the potential role of KARs in cerebellum-like structures, including the DCN and cerebellum, are poorly understood. In this review, we summarize the similarity between the DCN and cerebellum at the levels of structure, circuitry, and cell type as well as the investigations referring to the expression patterns of KARs in the DCN and cerebellum according to previous studies. Recent studies on the role of KARs have shown that KARs mediate a bidirectional modulatory effect at parallel fiber (PF)–Purkinje cell (PC) synapses in the cerebellum, implying insights into their roles in cerebellum-like structures, including the DCN, that remain to be explored in the coming years.

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Cerebellar Development and Circuit Maturation: A Common Framework for Spinocerebellar Ataxias

Cited by 9 publications

References 161 publications

BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination

BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination

Therapeutic Use of Cerebellar Intermittent Theta Burst Stimulation (iTBS) in a Sardinian Family Affected by Spinocerebellar Ataxia 38 (SCA 38)

Focusing on the Emerging Role of Kainate Receptors in the Dorsal Cochlear Nucleus (DCN) and Cerebellum

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