Activin A targets extrasynaptic NMDA receptors to ameliorate neuronal and behavioral deficits in a mouse model of Huntington disease
Cortical-striatal synaptic dysfunction, including enhanced toxic signaling by extrasynaptic N-methyl-d-aspartate receptors (eNMDARs), precedes neurodegeneration in Huntington disease (HD). A previous study showed Activin A, whose transcription is upregulated by calcium influx via synaptic NMDARs, su...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-12-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996123003765 |
| _version_ | 1797401730200109056 |
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| author | Wissam B. Nassrallah Daniel Ramandi Judy Cheng Jean Oh James Mackay Marja D. Sepers David Lau Hilmar Bading Lynn A. Raymond |
| author_facet | Wissam B. Nassrallah Daniel Ramandi Judy Cheng Jean Oh James Mackay Marja D. Sepers David Lau Hilmar Bading Lynn A. Raymond |
| author_sort | Wissam B. Nassrallah |
| collection | DOAJ |
| description | Cortical-striatal synaptic dysfunction, including enhanced toxic signaling by extrasynaptic N-methyl-d-aspartate receptors (eNMDARs), precedes neurodegeneration in Huntington disease (HD). A previous study showed Activin A, whose transcription is upregulated by calcium influx via synaptic NMDARs, suppresses eNMDAR signaling. Therefore, we examined the role of Activin A in the YAC128 HD mouse model, comparing it to wild-type controls. We found decreased Activin A secretion in YAC128 cortical-striatal co-cultures, while Activin A overexpression in this model rescued altered eNMDAR expression. Striatal overexpression of Activin A in vivo improved motor learning on the rotarod task, and normalized striatal neuronal eNMDAR-mediated currents, membrane capacitance and spontaneous excitatory postsynaptic current frequency in the YAC128 mice. These results support the therapeutic potential of Activin A signaling and targeting eNMDARs to restore striatal neuronal health and ameliorate behavioral deficits in HD. |
| first_indexed | 2024-03-09T02:15:27Z |
| format | Article |
| id | doaj.art-04dd3efbeedd46cd91625a37365c615f |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-03-09T02:15:27Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-04dd3efbeedd46cd91625a37365c615f2023-12-07T05:27:45ZengElsevierNeurobiology of Disease1095-953X2023-12-01189106360Activin A targets extrasynaptic NMDA receptors to ameliorate neuronal and behavioral deficits in a mouse model of Huntington diseaseWissam B. Nassrallah0Daniel Ramandi1Judy Cheng2Jean Oh3James Mackay4Marja D. Sepers5David Lau6Hilmar Bading7Lynn A. Raymond8Graduate Program in Neuroscience, University of British Columbia, Canada; University of British Columbia, Vancouver, BC, Canada; Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, CanadaGraduate Program in Cell and Developmental Biology, University of British Columbia, Canada; Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, CanadaGraduate Program in Neuroscience, University of British Columbia, Canada; Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, CanadaDepartment of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, CanadaDepartment of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, CanadaDepartment of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, CanadaDepartment of Neurobiology, Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, GermanyDepartment of Neurobiology, Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, GermanyDepartment of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Canada; Department of Medicine, Division of Neurology, University of British Columbia, Canada; Corresponding author at: Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Canada.Cortical-striatal synaptic dysfunction, including enhanced toxic signaling by extrasynaptic N-methyl-d-aspartate receptors (eNMDARs), precedes neurodegeneration in Huntington disease (HD). A previous study showed Activin A, whose transcription is upregulated by calcium influx via synaptic NMDARs, suppresses eNMDAR signaling. Therefore, we examined the role of Activin A in the YAC128 HD mouse model, comparing it to wild-type controls. We found decreased Activin A secretion in YAC128 cortical-striatal co-cultures, while Activin A overexpression in this model rescued altered eNMDAR expression. Striatal overexpression of Activin A in vivo improved motor learning on the rotarod task, and normalized striatal neuronal eNMDAR-mediated currents, membrane capacitance and spontaneous excitatory postsynaptic current frequency in the YAC128 mice. These results support the therapeutic potential of Activin A signaling and targeting eNMDARs to restore striatal neuronal health and ameliorate behavioral deficits in HD.http://www.sciencedirect.com/science/article/pii/S0969996123003765Striatal medium-sized spiny neuronSynapsePatch clamp recordingGlutamatergic neurotransmission |
| spellingShingle | Wissam B. Nassrallah Daniel Ramandi Judy Cheng Jean Oh James Mackay Marja D. Sepers David Lau Hilmar Bading Lynn A. Raymond Activin A targets extrasynaptic NMDA receptors to ameliorate neuronal and behavioral deficits in a mouse model of Huntington disease Neurobiology of Disease Striatal medium-sized spiny neuron Synapse Patch clamp recording Glutamatergic neurotransmission |
| title | Activin A targets extrasynaptic NMDA receptors to ameliorate neuronal and behavioral deficits in a mouse model of Huntington disease |
| title_full | Activin A targets extrasynaptic NMDA receptors to ameliorate neuronal and behavioral deficits in a mouse model of Huntington disease |
| title_fullStr | Activin A targets extrasynaptic NMDA receptors to ameliorate neuronal and behavioral deficits in a mouse model of Huntington disease |
| title_full_unstemmed | Activin A targets extrasynaptic NMDA receptors to ameliorate neuronal and behavioral deficits in a mouse model of Huntington disease |
| title_short | Activin A targets extrasynaptic NMDA receptors to ameliorate neuronal and behavioral deficits in a mouse model of Huntington disease |
| title_sort | activin a targets extrasynaptic nmda receptors to ameliorate neuronal and behavioral deficits in a mouse model of huntington disease |
| topic | Striatal medium-sized spiny neuron Synapse Patch clamp recording Glutamatergic neurotransmission |
| url | http://www.sciencedirect.com/science/article/pii/S0969996123003765 |
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