Biology subjects

King, G. D.

Publications and source records attributed to King, G. D..

3 recordsLinked to original sources

bioRxiv2022

Circadian regulation of dentate gyrus excitability mediated by G-protein signaling

The central circadian regulator within the suprachiasmatic nucleus transmits time of day information by a diurnal spiking rhythm that is driven by intrinsic activity of molecular clock genes controlling membrane excitability. Most brain regions, including the hippocampus, harbor similar intrinsic circadian transcriptional machinery but whether these molecular programs generate oscillations of membrane properties is unexplored. Here, we show that intrinsic excitability of mouse dentate granule neurons exhibits a 24-hour oscillation that controls spiking probability. Diurnal changes in excitability are mediated by antiphase G-protein regulation of potassium and sodium conductances to reduce excitability during the light phase. Disruption of the circadian transcriptional machinery by conditional deletion of Bmal1 enhances excitability selectively during the light phase, increasing engram recruitment and spatial discrimination memory. These results reveal that circadian transcriptional machinery regulates intrinsic excitability, highlighting the role of cell-autonomous oscillations in hippocampal function and behavior. HighlightsDentate neurons exhibit a 24-hour oscillation of excitability with low excitability during the Light phase Reduced excitability results from G-protein regulation of passive and active properties Bmal1 deletion disrupts G-protein regulation to enhance excitability during the Light Bmal1 deletion enhances the size of memory engrams and spatial discrimination

neuroscience↗

bioRxiv2019

Dengue after Zika: characterizing impacts of Zika emergence on endemic dengue transmission

In 2015 and 2016, Zika virus (ZIKV) swept through many Latin American countries where dengue virus (DENV) is endemic. Dengue and Zika viruses are of the same family, share a vector and may interact competitively or synergistically through human immune responses. We examine dengue incidence data from Brazil and Colombia from before, during, and after the Zika epidemic. We find evidence that dengue incidence was atypically low in 2017 in both Brazil and Colombia. We investigate whether Zika incidence at the state or department level is associated with changes in dengue incidence and find mixed results. We use simulations to investigate expected impact of cross-protection or enhancement between dengue and Zika. Our simulations show that regardless of the mechanism, low periods of dengue incidence are followed by a resurgence in dengue cases. It is therefore likely that countries currently experiencing low levels of dengue incidence will experience large dengue seasons in the near future. By considering multiple combinations of DENV and ZIKV reproduction numbers, we demonstrate that the mixed results of our statistical models are not entirely unexpected. Correlations in DENV and ZIKV reproduction number could contribute to complicating or masking an association between their case counts.

epidemiology↗

bioRxiv2019

A chromatin modulator sustains self-renewal and enables differentiation of postnatal neural stem and progenitor cells

It remains unknown whether H3K4 methylation, an epigenetic modification associated with gene activation, regulates fate determination of the postnatal neural stem and progenitor cells (NSCs and NPCs, or NSPCs). Here we show that the Dpy30 subunit of the major H3K4 methyltransferase complexes is preferentially expressed at a high level in NSCs and NPCs. By genetically inactivating Dpy30 in specific regions of mouse brain, we demonstrate a crucial role of efficient H3K4 methylation in maintaining both the self-renewal and differentiation capacity of postnatal NSPCs. Dpy30 inactivation results in deficiency in global H3K4 methylation, and disrupts development of hippocampus and especially the dentate gyrus and subventricular zone, the major regions for postnatal NSC activities. By in vitro assays on neurospheres from mouse brains as well as human and mouse NPCs, we show that Dpy30 is indispensable for sustaining the self-renewal and proliferation of NSPCs in a cell-intrinsic manner, and also enables the differentiation of mouse and human NPCs to neuronal and glial lineages. Dpy30 directly regulates H3K4 methylation and the induction of several genes critical in neurogenesis. These findings link a prominent epigenetic mechanism of gene expression to the fundamental properties of NSPCs, and may have implications in neurodevelopmental disorders. SIGNIFICANCE STATEMENTAs a highly prominent epigenetic mark that is associated with gene activation and a number of neurodevelopmental disorders in human, the role of histone H3K4 methylation in the fate determination of neural stem cells is unclear. Result of this study uncover a profound role of this epigenetic modification in the fundamental properties of postnatal neural stem cells, including self-renewal and differentiation, and may have implications for a better understanding and treatment of a broad spectrum of neurodevelopmental disorders associated with H3K4 methylation modulators.

developmental biology↗