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SorCS2 Is Important for Astrocytic Function in Neurovascular Signaling.

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Title: SorCS2 Is Important for Astrocytic Function in Neurovascular Signaling.
Authors: Staehr, Christian (AUTHOR), Login, Hande (AUTHOR), Melnikova, Elizaveta V. (AUTHOR), Bakun, Magdalena (AUTHOR), Ziemlinska, Ewelina (AUTHOR), Kisiswa, Lilian (AUTHOR), Ardestani, Simin Berenji (AUTHOR), Nolte, Stella Solveig (AUTHOR), Beck, Hans Christian (AUTHOR), Hansen, Line Mathilde Brostrup (AUTHOR), Postnov, Dmitry (AUTHOR), Verkhratsky, Alexei (AUTHOR), Malik, Anna R. (AUTHOR), Nykjaer, Anders (AUTHOR), Matchkov, Vladimir V. (AUTHOR)
Source: Acta Physiologica. Jun2025, Vol. 241 Issue 6, p1-15. 15p.
Subjects: Astrocytes, Glutamate receptors, Cerebral circulation, Drug receptors, Proteomics, Intracellular calcium, Brain diseases, Immunostaining
Abstract: Introduction: The receptor SorCS2 is involved in the trafficking of membrane receptors and transporters. It has been implicated in brain disorders and has previously been reported to be indispensable for ionotropic glutamatergic neurotransmission in the hippocampus. Aim: We aimed to study the role of SorCS2 in the control of astrocyte‐neuron communication, critical for neurovascular coupling. Methods: Brain slices from P8 and 2‐month‐old wild‐type and SorCS2 knockout (Sorcs2−/−) mice were immunostained for SorCS2, GFAP, AQP4, IB4, and CD31. Neurovascular coupling was assessed in vivo using laser speckle contrast imaging and ex vivo in live brain slices loaded with calcium‐sensitive dye. Bulk and cell surface fraction proteomics was analyzed on freshly isolated and cultured astrocytes, respectively, and validated with Western blot and qPCR. Results: SorCS2 was strongly expressed in astrocytes, primarily in their endfeet, of P8 mice; however, it was sparsely represented in 2‐month‐old mice. Sorcs2−/− mice demonstrated reduced neurovascular coupling associated with a reduced astrocytic calcium response to neuronal excitation. No differences in vascularization or endothelium‐dependent relaxation ex vivo between the 2‐month‐old groups were observed. Proteomics suggested changes in glutamatergic signaling and suppressed calcium signaling in Sorcs2−/− brains from both P8 and 2‐month‐old mice. The increased abundance of glutamate metabotropic receptor 3 in Sorcs2−/− astrocytes was validated by PCR and Western blot. In cultured Sorcs2−/− astrocytes, AQP4 abundance was increased in the bulk lysate but reduced in the cell surface fraction, suggesting impaired trafficking. Conclusion: The results suggest that SorCS2 expression is important for the development of neurovascular coupling, at least in part by modulating glutamatergic and calcium signaling in astrocytes. [ABSTRACT FROM AUTHOR]
Copyright of Acta Physiologica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: SorCS2 Is Important for Astrocytic Function in Neurovascular Signaling.
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  Data: <searchLink fieldCode="AR" term="%22Staehr%2C+Christian%22">Staehr, Christian</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Login%2C+Hande%22">Login, Hande</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Melnikova%2C+Elizaveta+V%2E%22">Melnikova, Elizaveta V.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Bakun%2C+Magdalena%22">Bakun, Magdalena</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ziemlinska%2C+Ewelina%22">Ziemlinska, Ewelina</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kisiswa%2C+Lilian%22">Kisiswa, Lilian</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ardestani%2C+Simin+Berenji%22">Ardestani, Simin Berenji</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Nolte%2C+Stella+Solveig%22">Nolte, Stella Solveig</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Beck%2C+Hans+Christian%22">Beck, Hans Christian</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Hansen%2C+Line+Mathilde+Brostrup%22">Hansen, Line Mathilde Brostrup</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Postnov%2C+Dmitry%22">Postnov, Dmitry</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Verkhratsky%2C+Alexei%22">Verkhratsky, Alexei</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Malik%2C+Anna+R%2E%22">Malik, Anna R.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Nykjaer%2C+Anders%22">Nykjaer, Anders</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Matchkov%2C+Vladimir+V%2E%22">Matchkov, Vladimir V.</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Acta+Physiologica%22">Acta Physiologica</searchLink>. Jun2025, Vol. 241 Issue 6, p1-15. 15p.
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  Data: <searchLink fieldCode="DE" term="%22Astrocytes%22">Astrocytes</searchLink><br /><searchLink fieldCode="DE" term="%22Glutamate+receptors%22">Glutamate receptors</searchLink><br /><searchLink fieldCode="DE" term="%22Cerebral+circulation%22">Cerebral circulation</searchLink><br /><searchLink fieldCode="DE" term="%22Drug+receptors%22">Drug receptors</searchLink><br /><searchLink fieldCode="DE" term="%22Proteomics%22">Proteomics</searchLink><br /><searchLink fieldCode="DE" term="%22Intracellular+calcium%22">Intracellular calcium</searchLink><br /><searchLink fieldCode="DE" term="%22Brain+diseases%22">Brain diseases</searchLink><br /><searchLink fieldCode="DE" term="%22Immunostaining%22">Immunostaining</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Introduction: The receptor SorCS2 is involved in the trafficking of membrane receptors and transporters. It has been implicated in brain disorders and has previously been reported to be indispensable for ionotropic glutamatergic neurotransmission in the hippocampus. Aim: We aimed to study the role of SorCS2 in the control of astrocyte‐neuron communication, critical for neurovascular coupling. Methods: Brain slices from P8 and 2‐month‐old wild‐type and SorCS2 knockout (Sorcs2−/−) mice were immunostained for SorCS2, GFAP, AQP4, IB4, and CD31. Neurovascular coupling was assessed in vivo using laser speckle contrast imaging and ex vivo in live brain slices loaded with calcium‐sensitive dye. Bulk and cell surface fraction proteomics was analyzed on freshly isolated and cultured astrocytes, respectively, and validated with Western blot and qPCR. Results: SorCS2 was strongly expressed in astrocytes, primarily in their endfeet, of P8 mice; however, it was sparsely represented in 2‐month‐old mice. Sorcs2−/− mice demonstrated reduced neurovascular coupling associated with a reduced astrocytic calcium response to neuronal excitation. No differences in vascularization or endothelium‐dependent relaxation ex vivo between the 2‐month‐old groups were observed. Proteomics suggested changes in glutamatergic signaling and suppressed calcium signaling in Sorcs2−/− brains from both P8 and 2‐month‐old mice. The increased abundance of glutamate metabotropic receptor 3 in Sorcs2−/− astrocytes was validated by PCR and Western blot. In cultured Sorcs2−/− astrocytes, AQP4 abundance was increased in the bulk lysate but reduced in the cell surface fraction, suggesting impaired trafficking. Conclusion: The results suggest that SorCS2 expression is important for the development of neurovascular coupling, at least in part by modulating glutamatergic and calcium signaling in astrocytes. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Acta Physiologica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.1111/apha.70052
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      – Code: eng
        Text: English
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        PageCount: 15
        StartPage: 1
    Subjects:
      – SubjectFull: Astrocytes
        Type: general
      – SubjectFull: Glutamate receptors
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      – SubjectFull: Cerebral circulation
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      – SubjectFull: Drug receptors
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      – SubjectFull: Proteomics
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      – SubjectFull: Intracellular calcium
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      – SubjectFull: Brain diseases
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      – SubjectFull: Immunostaining
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      – TitleFull: SorCS2 Is Important for Astrocytic Function in Neurovascular Signaling.
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              Text: Jun2025
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