Parvalbumin Interneuron Vulnerability in Nervous System Injury and Disease
Ruden, Jacob Benjamin
0000-0002-9543-9088
:
2022-03-27
Abstract
Parvalbumin interneurons (PV-INs), a subset of inhibitory interneurons, are defined by their fast-spiking phenotype and by the presence of the calcium-binding protein parvalbumin. PV-INs are vulnerable to many stressors, including inflammation. Potential causes of PV-IN vulnerability include their unique energy requirements, strong excitatory drive, and complex developmental trajectory. PV-IN-related changes have been observed in individuals with schizophrenia, bipolar disorder, autism spectrum disorder, and Alzheimer’s disease. PV-INs rely on NMDA receptors to function properly. Using an accelerated protocol, human neural progenitor cells were converted into neurons. RT-PCR and Western blot experiments confirmed that markers of mature NMDA receptors were present in the neurons, and calcium imaging and whole-cell voltage clamp electrophysiology experiments confirmed that the NMDA receptors were functional. This allowed for a source of human PV-INs to be available for future pro-inflammatory experiments, as there are key differences between primate and rodent neurons. The PVcre-tdTomato mouse model, which allows for the identification of PV-INs irrespective of the presence of parvalbumin immunostaining, was generated to distinguish PV-IN injury from PV-IN degeneration. PVcre-tdTomato mice were exposed to chronic hypoxia or normoxia. Levels of the pro-inflammatory cytokine IL-6 were elevated in mice exposed to chronic hypoxia, indicating that inflammation was induced. Confocal imaging and analysis of hippocampal slices from PVcre-tdTomato mice revealed that chronic hypoxia resulted in PV-IN injury but not degeneration. Calretinin interneurons, another subset of inhibitory interneurons, were not injured by exposure to chronic hypoxia, indicating that PV-INs were more vulnerable to this pro-inflammatory stimulus. The existence of dysfunctional PV-INs that remain alive highlights the potential for PV-IN functional rescue after injury due to a pro-inflammatory insult.