Parvalbumin expression in oligodendrocyte-like CG4 cells causes a reduction in mitochondrial volume, attenuation in reactive oxygen species production and a decrease in cell processes’ length and branching
Abstract:Forebrain glial cells - ependymal cells and astrocytes -acquire upon injury- a “reactive” phenotype associated with parvalbumin (PV) upregulation. Since free radicals, e.g. reactive oxygen species (ROS) play a role in the pathogenesis of multiple sclerosis, and that PV-upregulation in glial cells is inversely correlated with the level of oxidative stress, we hypothesized that PV-upregulation might also protect oligodendrocytes by decreasing ROS production. Lentiviral transduction techniques allowed for PV over… Show more
“…In distinct Pvalb neuron populations in adult PV−/− mice, the mitochondrial volume is augmented and the relative increase strongly correlates with the PV concentration prevailing in the various WT Pvalb neuron subpopulations in the different brain regions, i.e., the higher the concentration of PV, the higher the PV loss-induced increase in mitochondria volume ( Janickova et al, 2020 ). Interestingly, both in CG4 cells and more relevant in PV−/− Pvalb neurons, the increase in mitochondria volume and dendritic mitochondria length is associated with increased branching and length of dendrites ( Lichvarova et al, 2019 ; Janickova et al, 2020 ), in full agreement with the reported increase in genes of module cM1 (‘morphogenesis of branching structures’) in three ASD and schizophrenia mouse models ( Gordon et al, 2019 ). Thus, we set out to investigate the timeline of events caused by the absence of PV.…”
Section: Introductionsupporting
confidence: 78%
“…The volume of the cytoplasm, nuclei and mitochondria were calculated for each neuron using the same parameter and algorithm settings. Statistical analyses were performed using the ‘Imaris Measurement Pro’ module as described previously ( Lichvarova et al, 2019 ).…”
In neurodevelopmental disorders (NDDs) including autism spectrum disorder (ASD) and schizophrenia, impairment/malfunctioning of a subpopulation of interneurons expressing the calcium-binding protein parvalbumin (PV) –here termed Pvalb neurons– has gradually emerged as a possible cause. These neurons may represent a hub or point-of-convergence in the etiology of NDD. Increased oxidative stress associated with mitochondria impairment in Pvalb neurons is discussed as an essential step in schizophrenia etiology. Since PV downregulation is a common finding in ASD and schizophrenia individuals and PV-deficient (PV−/−) mice show a strong ASD-like behavior phenotype, we investigated the putative link between PV expression, alterations in mitochondria and oxidative stress. In a longitudinal study with 1, 3, and 6-months old PV−/− and wild type mice, oxidative stress was investigated in 9 Pvalb neuron subpopulations in the hippocampus, striatum, somatosensory cortex, medial prefrontal cortex, thalamic reticular nucleus (TRN) and cerebellum. In Pvalb neuron somata in the striatum and TRN, we additionally determined mitochondria volume and distribution at these three time points. In all Pvalb neuron subpopulations, we observed an age-dependent increase in oxidative stress and the increase strongly correlated with PV expression levels, but not with mitochondria density in these Pvalb neurons. Moreover, oxidative stress was elevated in Pvalb neurons of PV−/− mice and the magnitude of the effect was again correlated with PV expression levels in the corresponding wild type Pvalb neuron subpopulations. The PV-dependent effect was insignificant at 1 month and relative differences between WT and PV−/− Pvalb neurons were largest at 3 months. Besides the increase in mitochondria volume in PV’s absence in TRN and striatal PV−/− Pvalb neurons fully present already at 1 month, we observed a redistribution of mitochondria from the perinuclear region toward the plasma membrane at all time points. We suggest that in absence of PV, slow Ca
2+
buffering normally exerted by PV is compensated by a (mal)adaptive, mostly sub-plasmalemmal increase in mitochondria resulting in increased oxidative stress observed in 3- and 6-months old mice. Since PV−/− mice display core ASD-like symptoms already at 1 month, oxidative stress in Pvalb neurons is not a likely cause for their ASD-related behavior observed at this age.
“…In distinct Pvalb neuron populations in adult PV−/− mice, the mitochondrial volume is augmented and the relative increase strongly correlates with the PV concentration prevailing in the various WT Pvalb neuron subpopulations in the different brain regions, i.e., the higher the concentration of PV, the higher the PV loss-induced increase in mitochondria volume ( Janickova et al, 2020 ). Interestingly, both in CG4 cells and more relevant in PV−/− Pvalb neurons, the increase in mitochondria volume and dendritic mitochondria length is associated with increased branching and length of dendrites ( Lichvarova et al, 2019 ; Janickova et al, 2020 ), in full agreement with the reported increase in genes of module cM1 (‘morphogenesis of branching structures’) in three ASD and schizophrenia mouse models ( Gordon et al, 2019 ). Thus, we set out to investigate the timeline of events caused by the absence of PV.…”
Section: Introductionsupporting
confidence: 78%
“…The volume of the cytoplasm, nuclei and mitochondria were calculated for each neuron using the same parameter and algorithm settings. Statistical analyses were performed using the ‘Imaris Measurement Pro’ module as described previously ( Lichvarova et al, 2019 ).…”
In neurodevelopmental disorders (NDDs) including autism spectrum disorder (ASD) and schizophrenia, impairment/malfunctioning of a subpopulation of interneurons expressing the calcium-binding protein parvalbumin (PV) –here termed Pvalb neurons– has gradually emerged as a possible cause. These neurons may represent a hub or point-of-convergence in the etiology of NDD. Increased oxidative stress associated with mitochondria impairment in Pvalb neurons is discussed as an essential step in schizophrenia etiology. Since PV downregulation is a common finding in ASD and schizophrenia individuals and PV-deficient (PV−/−) mice show a strong ASD-like behavior phenotype, we investigated the putative link between PV expression, alterations in mitochondria and oxidative stress. In a longitudinal study with 1, 3, and 6-months old PV−/− and wild type mice, oxidative stress was investigated in 9 Pvalb neuron subpopulations in the hippocampus, striatum, somatosensory cortex, medial prefrontal cortex, thalamic reticular nucleus (TRN) and cerebellum. In Pvalb neuron somata in the striatum and TRN, we additionally determined mitochondria volume and distribution at these three time points. In all Pvalb neuron subpopulations, we observed an age-dependent increase in oxidative stress and the increase strongly correlated with PV expression levels, but not with mitochondria density in these Pvalb neurons. Moreover, oxidative stress was elevated in Pvalb neurons of PV−/− mice and the magnitude of the effect was again correlated with PV expression levels in the corresponding wild type Pvalb neuron subpopulations. The PV-dependent effect was insignificant at 1 month and relative differences between WT and PV−/− Pvalb neurons were largest at 3 months. Besides the increase in mitochondria volume in PV’s absence in TRN and striatal PV−/− Pvalb neurons fully present already at 1 month, we observed a redistribution of mitochondria from the perinuclear region toward the plasma membrane at all time points. We suggest that in absence of PV, slow Ca
2+
buffering normally exerted by PV is compensated by a (mal)adaptive, mostly sub-plasmalemmal increase in mitochondria resulting in increased oxidative stress observed in 3- and 6-months old mice. Since PV−/− mice display core ASD-like symptoms already at 1 month, oxidative stress in Pvalb neurons is not a likely cause for their ASD-related behavior observed at this age.
“…This specific potassium channel subunit composition is almost exclusively expressed within PV neurons and changes when the level of PV decreases [50]. PV levels are also inversely related to cell and mitochondria volume and reactive oxygen species (ROS) production [52][53][54][55], suggesting that the conditioned effects of cocaine-associated memory reactivation could decrease PV through ROS production. Additionally, GAD 67 levels are correlated with NMDAR subunit composition [56].…”
Perineuronal nets (PNNs) are specialized extracellular matrix structures that ensheathe parvalbumin-containing fast-spiking interneurons (PV FSIs) and play a key role in neuroplasticity. We previously showed that PNNs within the prelimbic prefrontal cortex (PL PFC) are required for the maintenance of cocaine-associated memories following cocaine memory reactivation. However, how cocaine memory reactivation affects PNNs, PV, and corresponding changes in PV FSI function are unknown. In this study, we characterized the electrophysiological properties of PV FSIs and corresponding changes in PNN and PV intensity within the PL PFC prior to and after cocaine memory reactivation. Adult male Sprague-Dawley rats were trained to acquire cocaine-conditioned place preference (CPP) and, following cocaine-CPP memory reactivation (30 m, 2 h, and 24 h post-reactivation), we measured PNN intensity (determined by Wisteria floribunda agglutinin [WFA] staining) as well as PV intensity using immunohistochemistry. The intensity of PV staining was reduced at all time points following memory reactivation with no changes in WFA intensity. Using whole-cell electrophysiology we found a reduction in the number of action potentials at 30 m and 2 h that returned to control levels by 24 h. The attenuation in firing was accompanied by a presumed compensatory increase in excitatory synaptic transmission, which was corroborated by an increase in VGluT1 puncta apposing PV/PNN neurons. Collectively, our results indicate that cocaine memory reactivation decreases PV intensity, which may play a role in decreasing excitation of PV FSIs. Thus, the inhibitory tone onto pyramidal neurons may be decreased following memory reactivation, resulting in an increase in PFC output to promote cocaine-seeking behaviors.
“…6A, B and 7A, B. All movie files are available in the ZENODO repository https ://doi.org/10.5281/zenod o.39072 89 1 . The individual frames from which the representative cells were taken are marked and annotated in the "Supporting Information" (.pdf) file available in the same repository.…”
mentioning
confidence: 99%
“…1A, B, G, and H could not be identified. A revised version of Figure 1 appears below, with the corresponding movies, which are available in the ZENODO repository https://doi.org/10.5281/zenodo.3907289 1 , referenced in the figure legend. Figure 1 CG4 cells display an OPCs-like morphology in the undifferentiated state ( A ) and oligodendrocyte-like phenotype in the differentiated state ( B ).…”
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