Staehr Christian, Login Hande, Melnikova Elizaveta V, Bakun Magdalena, Ziemlinska Ewelina, Kisiswa Lilian, Ardestani Simin Berenji, Nolte Stella Solveig, Beck Hans Christian, Hansen Line Mathilde Brostrup, Postnov Dmitry, Verkhratsky Alexei, Malik Anna R, Nykjaer Anders, Matchkov Vladimir V
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Department of Anaesthesiology and Intensive Care, Aarhus University Hospital, Aarhus, Denmark.
Acta Physiol (Oxf). 2025 Jun;241(6):e70052. doi: 10.1111/apha.70052.
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.
We aimed to study the role of SorCS2 in the control of astrocyte-neuron communication, critical for neurovascular coupling.
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.
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.
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.
受体SorCS2参与膜受体和转运体的运输。它与脑部疾病有关，此前有报道称其对海马体中的离子型谷氨酸能神经传递不可或缺。
我们旨在研究SorCS2在控制星形胶质细胞 - 神经元通讯中的作用，这对神经血管耦合至关重要。
对出生后8天（P8）和2个月大的野生型及SorCS2基因敲除（Sorcs2）小鼠的脑片进行免疫染色，检测SorCS2、胶质纤维酸性蛋白（GFAP）、水通道蛋白4（AQP4）、IB4和CD31。使用激光散斑对比成像在体内评估神经血管耦合，并在加载钙敏染料的活脑片中进行体外评估。分别对新鲜分离和培养的星形胶质细胞进行整体和细胞表面部分蛋白质组学分析，并用蛋白质免疫印迹法和定量聚合酶链反应（qPCR）进行验证。
SorCS2在P8小鼠的星形胶质细胞中强烈表达，主要在其终足；然而，在2个月大的小鼠中表达稀少。Sorcs2小鼠表现出神经血管耦合减少，这与星形胶质细胞对神经元兴奋的钙反应降低有关。在2个月大的两组之间未观察到体外血管生成或内皮依赖性舒张的差异。蛋白质组学表明，P8和2个月大的Sorcs2小鼠大脑中的谷氨酸能信号传导发生变化，钙信号传导受到抑制。通过PCR和蛋白质免疫印迹法验证了Sorcs2星形胶质细胞中代谢型谷氨酸受体3丰度的增加。在培养的Sorcs2星形胶质细胞中，整体裂解物中AQP4丰度增加，但细胞表面部分减少，表明运输受损。
结果表明，SorCS2的表达对神经血管耦合的发育很重要，至少部分是通过调节星形胶质细胞中的谷氨酸能和钙信号传导来实现的。
