Mechanisms of Neuronal Dysfunction and Death in Sepsis-induced Cognitive Impairment
Clinical Neurology; Neurosurgery and Neuroradiology
Final Report Abstract
In the present project, we have used peripheral LPS injection as a model of experimental sepsis and performed molecular, cellular and behavioural analyses in wild type C57BL/6 mice, homozygous Mfge8, Mertk and Cd11b knockout mice. The data presented here confirm that peripheral LPS injections stimulate the innate immune system in the brain, as indicated by increased cytokines, C3 concentrations and microglia volume. Importantly, these measures of inflammation were not modulated by knockout/loss of function of Mertk, Mfge8 or Cd11b, enabling us to assess whether loss of phagocytic functions can affect pathological alterations after experimental sepsis. In this regard, it appears that sepsis-induced synapse loss and increased synaptic pruning in Mfge8 and Cd11b wildtype mice was at least partly prevented in their corresponding knockout mice. The data presented here confirm that deficiency of the phagocytic receptor protein MERTK was beneficial for cognitive function following LPS treatment, as indicated by reduced spatial learning and memory deficits. Likewise, lack of the phagocytic opsonin MFG-E8 reduced avoidance learning and retention memory deficits. Furthermore, our data supported evidence that neuroinflammation could last for a week in old mice following peripheral LPS injection. We also presented evidence against the irreversible changes in the density of pyramidal cells, inhibitory neurons and myelin proteins in the hippocampus. We found a significant loss of excitatory synaptic puncta in CA3 in the hippocampus 2 months after the LPS treatment. Our data suggest that the synapse loss was a region-specific, delayed response to LPS injection. Furthermore, our analysis revealed the simultaneous decrease of the complement C3 puncta in CA3 2 months after LPS treatment and normal or reduced synaptic pruning by CA1 and CA3 microglia at 7 and 63 days post LPS injection. However, contrary to our expectations, no cellular correlate of long-term cognitive impairments, e.g. persistent reduction in synapse number or increased phagocytosis, was evident in the immunohistochemical analysis of the Mertk, Mfge8 or Cd11b knockout mouse brains. While a restructuring of synapses (i.e. enhanced survival of synapses and their replacement with new but possibly functionally less relevant synapses) may be sufficient to affect brain function, this remains to be demonstrated. Future work may focus on assessing the effect of phagocytic deficiency in peripheral LPS injection model to enhance the translatability of our findings into new therapeutic strategies for human sepsis survivors. Furthermore, it remained elusive how and when the region-specific, delayed synapse loss had occurred. A more detailed investigation of the MFG-E8 pathway may inform our understanding of the molecular mechanisms of brain dysfunction following sepsis.
Publications
- Body temperature measurement in mice during acute illness: Implantable temperature transponder versus surface infrared thermometry. Scientific Reports, Feburary 2018, 3526, volume 8(1)
Mei, J., Riedel, N., Grittner, U., Endres, M., Banneke, S., Emmrich, J.V.
(See online at https://doi.org/10.1038/s41598-018-22020-6) - Refining humane endpoints in mouse models of disease by systematic review and machine learning-based endpoint definition. ALTEX- Alternatives to Animal Experimentation, April 2019, 555-571, volume 36(4)
Mei, J., Banneke, S., Lips, J., Kuffner, M., Hoffmann, C., Dirnagl, U., Endres, M., Harms, C., Emmrich, J.V.
(See online at https://doi.org/10.14573/altex.1812231) - Automated radial 8-arm maze: A voluntary and stress-free behavior test to assess spatial learning and memory in mice. Behavioural Brain Research, March 2020, 112352, volume 381
Mei, J., Kohler, J., Winter, Y., Spies, C., Endres, M., Banneke, S., Emmrich, J.V.
(See online at https://doi.org/10.1016/j.bbr.2019.112352)
