Biology subjects

Wei Wei

Publications and source records attributed to Wei Wei.

3 recordsLinked to original sources

bioRxiv2020

Wide phenotypic spectrum of human stem cell-derived excitatory neurons with Rett syndrome-associated MECP2 mutations

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by heterozygous loss-of-function mutations in the X-linked gene MECP2 that is a global transcriptional regulator. Mutations in the methyl-CpG binding domain (MBD) of MECP2 disrupt its interaction with methylated DNA. Here, we investigate the effect of MECP2 L124W missense mutation in the MBD of an atypical RTT patient in comparison to severe MECP2 null mutations. L124W protein had a limited ability to disrupt heterochromatic chromocenters due to decreased binding dynamics. We isolated two pairs of isogenic WT and L124W induced pluripotent stem cells. L124W induced excitatory neurons expressed stable protein, exhibited increased input resistance and decreased voltage-gated Na+ and K+ currents, and their neuronal dysmorphology was limited to decreased dendritic complexity. Three isogenic pairs of MECP2 null neurons had the expected more extreme morphological and electrophysiological phenotypes. We examined development and maturation of L124W and MECP2 null excitatory neural network activity using micro-electrode arrays. Relative to isogenic controls, L124W neurons had an increase in synchronous network burst frequency, in contrast to MECP2 null neurons that suffered a significant decrease in synchronous network burst frequency and a transient extension of network burst duration. We capture these findings in a computational neural network model that shows the observed changes in network dynamics are best explained by changes in intrinsic adaptation currents in individual neurons. Our multilevel results demonstrate that RTT excitatory neurons show a wide spectrum of morphological, electrophysiological and circuitry phenotypes that are dependent on the severity of the MECP2 mutation.

neuroscience↗

bioRxiv2016

The formation of extinction memory requires the accumulation of N6-methyl-2-deoxyadenosine in DNA

Here we report that the recently discovered mammalian DNA modification N6-methyl-2-deoxyadenosine (m6dA) is dynamically regulated in primary cortical neurons, and accumulates along promoters and coding sequences within the genome of activated prefrontal cortical neurons of adult C57/BI6 mice in response to fear extinction learning. The deposition of m6dA is generally associated with increased genome-wide occupancy of the mammalian m6dA methyltransferase, N6amt1, and this correlates with fear extinction learning-induced gene expression. Of particular relevance for fear extinction memory, the accumulation of m6dA is associated with an active chromatin state and the recruitment of transcriptional machinery to the brain-derived neurotrophic factor (Bdnf) P4 promoter, which is required for Bdnf exon IV mRNA expression and for the extinction of conditioned fear. These results expand the scope of DNA modifications in the adult brain and highlight changes in m6dA as a novel neuroepigenetic mechanism associated with activity-induced gene expression and the formation of fear extinction memory.

Neuroscience↗

bioRxiv2015

Connectome of a model local cortical circuit flexibly shapes layer-dependent multi-frequency oscillations

The role played by interlayer connections in shaping local responses and their long-range coupling has not yet been fully elucidated. Here, we analyze a rate model of a canonic local circuit with realistic anatomy. We find that this circuit generates a rich repertoire of possible dynamical states, including an oscillatory regime in which gamma-and beta-oscillations dominate in superficial and deep layers, respectively, in agreement with experimental observations. This regime stems from non-linear inter-layer interactions, independently from intrinsic resonance properties of distinct layers. Moreover, by connecting two local circuits via cortico-cortical projections, the emergent phase differences define a flexible and frequency-dependent inter-areal hierarchy. Such dynamic patterns generally do not arise in randomized circuits, and the compatible connectomes are rare, although not unique. Altogether, these results suggest that inter-layer connectivity is homeostatically regulated to make local circuits fit to integrate and multiplex signals from several sources in multiple frequency bands.\n\nAuthor SummaryThe local circuit of mammalian cortex presents a characteristic multilayered structure, with feedforward (and feedback) cortico-cortical connections originating from (and targeting) distinct and well defined layers. Here, we model how such a structure fundamentally shapes the dynamical repertoire of local cortical oscillatory states and their long-range interaction. Experimental evidence, matched by our simulations, suggests that different cortical layers oscillate at different frequencies and that neuronal oscillations at different frequencies are exploited for communication in different directions. While this laminar specificity of oscillations is often explained in terms of multiple inhibitory populations with different resonance properties, we show here that it could alternatively emerge as a byproduct of the collective local circuit dynamics. Our modelling study indicates furthermore that the empirically observed multi-frequency oscillatory patterns cannot be reproduced in presence of an arbitrary interlayer connectivity. In this sense, therefore, we believe that the adopted connectome, derived from neuroanatomical reconstructions, is \"special\". Nevertheless, it is not unique, since other, very different connectomes may also lead to a matching dynamical repertoire. This suggests that a multiplicity of non-random canonical circuit templates may share largely overlapping functions, robustly achieved and maintained via functional homeostasis mechanisms.

Neuroscience↗