Cerebellar Ataxia Caused by Type II Unipolar Brush Cell Dysfunction in the Asic5 Knockout Mouse

Kreko‐Pierce, Tabita; Boiko, Nina; Harbidge, Donald G.; Marcus, Daniel C.; Stockand, James D.; Pugh, Jason R.

doi:10.1038/s41598-020-58901-y

Cited by 11 publications

(7 citation statements)

References 45 publications

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“…Unipolar brush cells are small, Eomes/TBR2 positive (Figure 1 and Figure S1) glutamatergic neurons, residing in the granular layer of the cerebellar cortex [38]. In Asic5 mutant mice, dysfunction of unipolar brush cells results in cerebellar ataxia [39]. Pathway analysis confirmed the glutamatergic signaling of these cells (Table S2).…”

Section: Neuronal Transcriptomesmentioning

confidence: 77%

Single Cell Transcriptome Analysis of Niemann–Pick Disease, Type C1 Cerebella

Cougnoux

Yerger

Fellmeth

et al. 2020

IJMS

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Niemann–Pick disease, type C1 (NPC1) is a lysosomal disease characterized by endolysosomal storage of unesterified cholesterol and decreased cellular cholesterol bioavailability. A cardinal symptom of NPC1 is cerebellar ataxia due to Purkinje neuron loss. To gain an understanding of the cerebellar neuropathology we obtained single cell transcriptome data from control (Npc1+/+) and both three-week-old presymptomatic and seven-week-old symptomatic mutant (Npc1−/−) mice. In seven-week-old Npc1−/− mice, differential expression data was obtained for neuronal, glial, vascular, and myeloid cells. As anticipated, we observed microglial activation and increased expression of innate immunity genes. We also observed increased expression of innate immunity genes by other cerebellar cell types, including Purkinje neurons. Whereas neuroinflammation mediated by microglia may have both neuroprotective and neurotoxic components, the contribution of increased expression of these genes by non-immune cells to NPC1 pathology is not known. It is possible that dysregulated expression of innate immunity genes by non-immune cells is neurotoxic. We did not anticipate a general lack of transcriptomic changes in cells other than microglia from presymptomatic three-week-old Npc1−/− mice. This observation suggests that microglia activation precedes neuronal dysfunction. The data presented in this paper will be useful for generating testable hypotheses related to disease progression and Purkinje neurons loss as well as providing insight into potential novel therapeutic interventions.

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Section: Neuronal Transcriptomesmentioning

confidence: 77%

Single Cell Transcriptome Analysis of Niemann–Pick Disease, Type C1 Cerebella

Cougnoux

Yerger

Fellmeth

et al. 2020

IJMS

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“…More detailed analysis revealed expression in unipolar brush border cells of the cerebellum [ 5 ] and cholangiocytes, the epithelial cells lining bile ducts in the liver [ 38 ]. In UBCs, BASIC seems to be involved in intrinsic excitability [ 17 ], and the physiological function of BASIC in cholangiocytes, however, is not understood. Various bile acids activate BASIC robustly and reversibly in heterologous cell systems with various potencies but concentrations in the millimolar range are required for strong activation of BASIC [ 38 , 22 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

The bile acid-sensitive ion channel (BASIC) mediates bile acid-dependent currents in bile duct epithelial cells

Wiegreffe

Löhrer

Wirtz

et al. 2021

Pflugers Arch - Eur J Physiol

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The bile acid-sensitive ion channel (BASIC) is a member of the Deg/ENaC family of ion channels that is activated by bile acids. Despite the identification of cholangiocytes in the liver and unipolar brush cells in the cerebellum as sites of expression, the physiological function of BASIC in these cell types is not yet understood. Here we used a cholangiocyte cell line, normal rat cholangiocytes (NRCs), which expresses BASIC to study the role of the channel in epithelial transport using Ussing chamber experiments. Apical application of bile acids induced robust and transient increases in transepithelial currents that were carried by Na+ and partly blocked by the BASIC inhibitor diminazene. Genetic ablation of the BASIC gene in NRC using a CRISPR-cas9 approach resulted in a decrease of the bile acid-mediated response that matched the diminazene-sensitive current in NRC WT cells, suggesting that cholangiocytes respond to bile acids with a BASIC-mediated Na+ influx. Taken together, we have identified BASIC as a component of the cholangiocyte transport machinery, which might mediate a bile acid-dependent modification of the bile and thus control bile flux and composition.

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“…UBCs are excitatory interneurons located in the granular layer that are usually innervated by a single MF ( Mugnaini and Floris, 1994 ). UBCs contribute to temporal processing by converting short-lived MF signals into long-lasting changes in UBC activity ( Kennedy et al, 2014 ; Kinney et al, 1997 ; Kreko-Pierce et al, 2020 ; Locatelli et al, 2013 ; Mugnaini and Floris, 1994 ; Mugnaini et al, 2011 ; Rossi et al, 1995 ; van Dorp and De Zeeuw, 2014 ). MFs excite UBCs that express metabotropic glutamate receptor type I (mGluR1), suppress firing in UBCs where mGluR2 is prominent, and evoke more complex responses in other UBCs that express both mGluR1 and mGluR2 ( Borges-Merjane and Trussell, 2015 ; Guo et al, 2021 ; Kinney et al, 1997 ; Knoflach and Kemp, 1998 ; Rossi et al, 1995 ; Russo et al, 2008 ; van Dorp and De Zeeuw, 2014 ; Zampini et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Purkinje cell outputs selectively inhibit a subset of unipolar brush cells in the input layer of the cerebellar cortex

Guo

Rudolph

Neuwirth

et al. 2021

eLife

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Circuitry of the cerebellar cortex is regionally and functionally specialized. Unipolar brush cells (UBCs), and Purkinje cell (PC) synapses made by axon collaterals in the granular layer, are both enriched in areas that control balance and eye movement. Here, we find a link between these specializations in mice: PCs preferentially inhibit metabotropic glutamate receptor type 1 (mGluR1)-expressing UBCs that respond to mossy fiber (MF) inputs with long lasting increases in firing, but PCs do not inhibit mGluR1-lacking UBCs. PCs inhibit about 29% of mGluR1-expressing UBCs by activating GABAA receptors (GABAARs) and inhibit almost all mGluR1-expressing UBCs by activating GABAB receptors (GABABRs). PC to UBC synapses allow PC output to regulate the input layer of the cerebellar cortex in diverse ways. Based on optogenetic studies and a small number of paired recordings, GABAAR-mediated feedback is fast and unreliable. GABABR-mediated inhibition is slower and is sufficiently large to strongly influence the input-output transformations of mGluR1-expressing UBCs.

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Cerebellar Ataxia Caused by Type II Unipolar Brush Cell Dysfunction in the Asic5 Knockout Mouse

Cited by 11 publications

References 45 publications

Single Cell Transcriptome Analysis of Niemann–Pick Disease, Type C1 Cerebella

Single Cell Transcriptome Analysis of Niemann–Pick Disease, Type C1 Cerebella

The bile acid-sensitive ion channel (BASIC) mediates bile acid-dependent currents in bile duct epithelial cells

Purkinje cell outputs selectively inhibit a subset of unipolar brush cells in the input layer of the cerebellar cortex

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