SorCS2

SorCS2, a receptor involved in protein trafficking, plays a key role in astrocyte-mediated neurovascular coupling (NVC) by regulating glutamatergic and calcium signaling pathways.

• SorCS2: Previously known for its role in glutamatergic neurotransmission, especially in the hippocampus.
• Neurovascular coupling (NVC): Critical mechanism by which neuronal activity leads to local blood flow increases, largely mediated by astrocytic endfeet.

• Models used: Sorcs2 knockout (Sorcs2-/-) vs wild-type mice.
• Ages: P8 (postnatal day 8) and 2-month-old mice.
• Techniques:
  • Immunohistochemistry (SorCS2, GFAP, AQP4, CD31…)
  • In vivo laser speckle contrast imaging for NVC.
  • Calcium imaging ex vivo in acute brain slices.
  • Proteomics (bulk + surface astrocyte proteome).
  • Western blot and qPCR validation.

• Expression Pattern:
  • SorCS2 is abundant in astrocytic endfeet in young (P8) mice, sparse in older mice.

• Functional Deficit:
• Sorcs2-/- mice have impaired NVC with reduced astrocytic calcium responses.

• Proteomic Changes:
  • Upregulation of glutamate receptor mGluR3 in Sorcs2-/- astrocytes.
  • Altered AQP4 distribution: ↑ in total lysate but ↓ on the cell surface.

• No vascular structural defects were observed, pointing to a functional rather than anatomical deficit.

• SorCS2 regulates astrocytic function via two mechanisms:
  1. Glutamatergic signaling modulation (likely feedback via mGluR3).
  2. Calcium signaling pathway stability, required for effective NVC.

• The mislocalization of AQP4 suggests trafficking defects, not expression-level defects.

1. Perioperative cerebral perfusion in patients with gliomas, trauma, or stroke might be influenced by astrocyte dysfunction and NVC defects.
2. Targeting astrocytic pathways like SorCS2 could be a future therapeutic avenue in neurodegenerative diseases or post-surgical edema management.

This study emphasizes the importance of early astrocytic regulation in developing NVC in pediatric neurosurgery, which is potentially relevant in congenital or early-onset encephalopathies.

• Strengths:
  • Multi-modal and cross-age analysis.
  • High technical rigor (proteomics + functional imaging).

• Limitations:
  • Lack of behavioral correlation.
  • Findings are mostly associative; mechanistic links (e.g., SorCS2 → mGluR3 trafficking) are implied, not directly tested

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