Deletion of LRP1 From Astrocytes Modifies Neuronal Network Activity in an in vitro Model of the Tripartite Synapse

Abstract

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.

Neural extracellular matrix regulates visual sensory motor integration

“…Furthermore, we noted a downregulation of Lrp1, an important modulator of the ECM [75]. Interestingly, deletion of Lrp1 from astrocytes in a hippocampal neuron co-culture model decreased neuronal network activity and influenced the proportion of pre-and postsynaptic structures [76]. In summary, we noted an extensive ECM remodeling and severe synaptic imbalance in quadruple mutant mice, which contribute to the impaired visual function and optomotor behavior.…”

Neural extracellular matrix regulates visual sensory motor integration

“… 79 Interestingly, deletion of Lrp1 from astrocytes in a hippocampal neuron co-culture model decreased neuronal network activity and influenced the proportion of pre- and postsynaptic structures. 80 In summary, we noted an extensive ECM remodeling and synaptic imbalance in quadruple mutant mice, which contribute to the impaired visual function and optomotor behavior.…”

Investigating the role that astrocytes play in mediating changes in synaptic health in Alzheimer’s disease

“…Alternatively, blocking endocytosis could cause Aβ to remain bound at the cell membrane (for example through binding to a receptor such as LRP1) for a prolonged period of time, which could have subsequent effects on intracellular signalling. Interestingly, differential levels of cytokines are observed in culture medium from neurons co-cultured with either wild type or LRP1-deficient astrocytes (Romeo et al, 2021), which suggests that LRP1 signalling in astrocytes may affect cytokine release. This is supported by another study, which found that LRP1 mediates Aβ-induced astrocyte activation, including the increased expression of the cytokine IL-1β (LaDu et al, 2000).…”