The low-density lipoprotein receptor-related protein 1 (LRP1) is a transmembrane receptor that binds over 40 potential ligands and is involved in processes such as cell differentiation, proliferation, and survival. LRP1 is ubiquitously expressed in the organism and enriched among others in blood vessels, liver, and the central nervous system (CNS). There, it is strongly expressed by neurons, microglia, immature oligodendrocytes, and astrocytes. The constitutive LRP1 knockout leads to embryonic lethality. Therefore, previous studies focused on conditional LRP1-knockout strategies and revealed that the deletion of LRP1 causes an increased differentiation of neural stem and precursor cells into astrocytes. Furthermore, astrocytic LRP1 is necessary for the degradation of Aβ and the reduced accumulation of amyloid plaques in Alzheimer’s disease. Although the role of LRP1 in neurons has intensely been investigated, the function of LRP1 with regard to the differentiation and maturation of astrocytes and their functionality is still unknown. To address this question, we generated an inducible conditional transgenic mouse model, where LRP1 is specifically deleted from GLAST-positive astrocyte precursor cells. The recombination with resulting knockout events was visualized by the simultaneous expression of the fluorescent reporter tdTomato. We observed a significantly increased number of GLT-1 expressing astrocytes in LRP1-depleted astrocytic cultures in comparison to control astrocytes. Furthermore, we investigated the influence of astrocytic LRP1 on neuronal activity and synaptogenesis using the co-culture of hippocampal neurons with control or LRP1-depleted astrocytes. These analyses revealed that the LRP1-deficient astrocytes caused a decreased number of single action potentials as well as a negatively influenced neuronal network activity. Moreover, the proportion of pre- and postsynaptic structures was significantly altered in neurons co-cultured with LPR1-depleted astrocytes. However, the number of structural synapses was not affected. Additionally, the supernatant of hippocampal neurons co-cultured with LRP1-deficient astrocytes showed an altered set of cytokines in comparison to the control condition, which potentially contributed to the altered neuronal transmission and synaptogenesis. Our results suggest astrocytic LRP1 as a modulator of synaptic transmission and synaptogenesis by altering the expression of the glutamate transporter on the cell surface on astrocytes and the release of cytokines in vitro.

低密度脂蛋白受体相关蛋白1（LRP1）是一种跨膜受体，可结合40多种潜在配体，并参与细胞分化，增殖和存活等过程。LRP1在生物体中普遍表达，并在血管，肝脏和中枢神经系统（CNS）中富集。在那里，它由神经元，小胶质细胞，未成熟少突胶质细胞和星形胶质细胞强烈表达。LRP1组成型敲除导致胚胎致死率。因此，先前的研究集中在条件LRP1敲除策略上，并发现LRP1的缺失导致神经干细胞和前体细胞向星形胶质细胞分化的增加。此外，星形细胞LRP1对于阿尔茨海默氏病中Aβ的降解和淀粉样斑块的减少的积累是必需的。尽管已经深入研究了LRP1在神经元中的作用，但是关于星形胶质细胞的分化和成熟及其功能，LRP1的功能仍然未知。为了解决这个问题，我们生成了可诱导的条件转基因小鼠模型，其中LRP1从GLAST阳性星形胶质细胞前体细胞中特异性缺失。通过同时表达荧光报告基因tdTomato，可以观察到重组和产生的敲除事件。我们观察到，与对照星形胶质细胞相比，在缺乏LRP1的星形细胞培养物中表达GLT-1的星形胶质细胞数量显着增加。此外，我们调查了星形胶质细胞LRP1对神经元活动和突触形成的影响，使用了海马神经元与对照或贫LRP1星形胶质细胞的共培养物。这些分析表明，缺乏LRP1的星形胶质细胞导致单动电位的降低以及对神经元网络活动的负面影响。此外，在与LPR1缺失的星形胶质细胞共培养的神经元中，突触前和突触后结构的比例显着改变。但是，结构突触的数量不受影响。另外，与对照条件相比，与缺乏LRP1的星形胶质细胞共培养的海马神经元上清液显示出一组改变的细胞因子，这可能导致改变的神经元传递和突触形成。我们的结果表明，星形胶质细胞LRP1通过改变星形胶质细胞表面上谷氨酸转运蛋白的表达和细胞因子的释放来调节突触传递和突触形成。体外。