Synaptic modulation of glutamate in striatum of the YAC128 mouse model of Huntington disease
Background: Altered balance between striatal direct and indirect pathways contributes to early motor, cognitive and psychiatric symptoms in Huntington disease (HD). While degeneration of striatal D2-type dopamine receptor (D2)-expressing indirect pathway medium spiny neurons (iMSNs) occurs prior to...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996124003760 |
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| author | Judy Cheng Ellen T. Koch Daniel Ramandi James P. Mackay Timothy P. O’Leary William Rees-Jones Lynn A. Raymond |
| author_facet | Judy Cheng Ellen T. Koch Daniel Ramandi James P. Mackay Timothy P. O’Leary William Rees-Jones Lynn A. Raymond |
| author_sort | Judy Cheng |
| collection | DOAJ |
| description | Background: Altered balance between striatal direct and indirect pathways contributes to early motor, cognitive and psychiatric symptoms in Huntington disease (HD). While degeneration of striatal D2-type dopamine receptor (D2)-expressing indirect pathway medium spiny neurons (iMSNs) occurs prior to that of D1-type dopamine receptor (D1)-expressing direct pathway neurons, altered corticostriatal synaptic function precedes degeneration. D2-mediated signaling on iMSNs reduces their excitability and promotes endocannabinoid (eCB) synthesis, suppressing glutamate release from cortical afferents. D2 receptors are also expressed on glutamatergic cortical terminals, cholinergic interneurons, and dopaminergic terminals from substantia nigra where they suppress release of glutamate, acetylcholine and dopamine, respectively, and these cell types may contribute to early striatal dysfunction in HD. Thus, we used corticostriatal brain slices and optogenetic probes to directly investigate neuromodulatory signaling in the transgenic YAC128 HD mouse model. Results: Low-dose D2 agonist quinpirole reduced cortically-evoked glutamate release in dorsal striatum of premanifest YAC128 slices but not WT, and blocking type 1 cannabinoid receptors mitigated this effect. YAC128 corticostriatal brain slices also showed increased evoked dopamine and reduced evoked eCB release compared to WT, while acetylcholine signaling patterns remained relatively intact. Conclusions: These findings suggest that YAC128 corticostriatal slices show increased D2 sensitivity that is eCB-dependent, and that dopamine and eCB release are altered at an early disease stage. We provide evidence for impaired neuromodulatory signaling in early HD, guiding therapeutic efforts prior to the onset of overt motor symptoms later on. |
| format | Article |
| id | doaj-art-233e64ef5d1a4c0ba1ec9175cdecb636 |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-233e64ef5d1a4c0ba1ec9175cdecb6362025-01-24T04:44:37ZengElsevierNeurobiology of Disease1095-953X2025-02-01205106774Synaptic modulation of glutamate in striatum of the YAC128 mouse model of Huntington diseaseJudy Cheng0Ellen T. Koch1Daniel Ramandi2James P. Mackay3Timothy P. O’Leary4William Rees-Jones5Lynn A. Raymond6Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada; Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, CanadaDepartment of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada; Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, CanadaDepartment of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada; Graduate Program in Cell and Developmental Biology, University of British Columbia, Vancouver, BC, CanadaDepartment of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, CanadaDepartment of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, CanadaDepartment of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, CanadaDepartment of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada; Corresponding author.Background: Altered balance between striatal direct and indirect pathways contributes to early motor, cognitive and psychiatric symptoms in Huntington disease (HD). While degeneration of striatal D2-type dopamine receptor (D2)-expressing indirect pathway medium spiny neurons (iMSNs) occurs prior to that of D1-type dopamine receptor (D1)-expressing direct pathway neurons, altered corticostriatal synaptic function precedes degeneration. D2-mediated signaling on iMSNs reduces their excitability and promotes endocannabinoid (eCB) synthesis, suppressing glutamate release from cortical afferents. D2 receptors are also expressed on glutamatergic cortical terminals, cholinergic interneurons, and dopaminergic terminals from substantia nigra where they suppress release of glutamate, acetylcholine and dopamine, respectively, and these cell types may contribute to early striatal dysfunction in HD. Thus, we used corticostriatal brain slices and optogenetic probes to directly investigate neuromodulatory signaling in the transgenic YAC128 HD mouse model. Results: Low-dose D2 agonist quinpirole reduced cortically-evoked glutamate release in dorsal striatum of premanifest YAC128 slices but not WT, and blocking type 1 cannabinoid receptors mitigated this effect. YAC128 corticostriatal brain slices also showed increased evoked dopamine and reduced evoked eCB release compared to WT, while acetylcholine signaling patterns remained relatively intact. Conclusions: These findings suggest that YAC128 corticostriatal slices show increased D2 sensitivity that is eCB-dependent, and that dopamine and eCB release are altered at an early disease stage. We provide evidence for impaired neuromodulatory signaling in early HD, guiding therapeutic efforts prior to the onset of overt motor symptoms later on.http://www.sciencedirect.com/science/article/pii/S0969996124003760Huntington diseaseStriatumCorticostriatal synapseGlutamateDopamineEndocannabinoids |
| spellingShingle | Judy Cheng Ellen T. Koch Daniel Ramandi James P. Mackay Timothy P. O’Leary William Rees-Jones Lynn A. Raymond Synaptic modulation of glutamate in striatum of the YAC128 mouse model of Huntington disease Neurobiology of Disease Huntington disease Striatum Corticostriatal synapse Glutamate Dopamine Endocannabinoids |
| title | Synaptic modulation of glutamate in striatum of the YAC128 mouse model of Huntington disease |
| title_full | Synaptic modulation of glutamate in striatum of the YAC128 mouse model of Huntington disease |
| title_fullStr | Synaptic modulation of glutamate in striatum of the YAC128 mouse model of Huntington disease |
| title_full_unstemmed | Synaptic modulation of glutamate in striatum of the YAC128 mouse model of Huntington disease |
| title_short | Synaptic modulation of glutamate in striatum of the YAC128 mouse model of Huntington disease |
| title_sort | synaptic modulation of glutamate in striatum of the yac128 mouse model of huntington disease |
| topic | Huntington disease Striatum Corticostriatal synapse Glutamate Dopamine Endocannabinoids |
| url | http://www.sciencedirect.com/science/article/pii/S0969996124003760 |
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