Biology subjects

ffrench-Constant, C.

Publications and source records attributed to ffrench-Constant, C..

4 recordsLinked to original sources

bioRxiv2023

Electroconvulsive stimuli reverse neuro-inflammation and behavioral deficits in a mouse model of depression.

BackgroundElectroconvulsive therapy is a fast, safe, and effective treatment for severe clinical depression but there is an ongoing search for mechanistic insights. MethodsWe used a mouse neuro-endocrine model of depression to examine behavioral, cellular, and molecular effects of electroconvulsive stimuli (ECS). ResultsThe behavioral response to repeated ECS correlated with adult neurogenesis, more strongly in the ventral than dorsal hippocampus. Subsequent RNA-seq analysis targeting the ventral subgranular zone (SGZ) delineated ECS-responsive molecular pathways that were shared between naive and depressive-state conditions, and which may represent core biological responses to seizure induction. Other pathways responded to ECS preferentially in the depressive state, suggesting further state- specific mechanisms. By comparing gene set pathways reciprocally altered in depressed-state animals then reversed by ECS, we identified and validated neuro-inflammation as a candidate regulator of the antidepressant response. We further identified 56 novel candidate antidepressant response genes in the ventral SGZ that may contribute to recovery, half of which have been implicated in human neuropsychiatric phenotypes. ConclusionsElectroconvulsive stimuli reverse neuro-inflammation in a mouse model of depression. The results offer a detailed molecular characterization of potential SGZ antidepressant response-specific genes and pathways in brain regions implicated in depression.

neuroscience↗

bioRxiv2022

Single nuclei RNAseq stratifies multiple sclerosis patients into three distinct white matter glia responses

The lack of understanding of the cellular and molecular basis of clinical and genetic heterogeneity in progressive multiple sclerosis (MS) has hindered the search for new effective therapies. Here, to address this gap, we analysed 632,000 single nuclei RNAseq profiles of 156 brain tissue samples, comprising white matter (WM) lesions, normal appearing WM, grey matter (GM) lesions and normal appearing GM from 54 MS patients and 26 controls. We observed the expected changes in overall neuronal and glial numbers previously described within the classical lesion subtypes. We found highly cell type-specific gene expression changes in MS tissue, with distinct differences between GM and WM areas, confirming different pathologies. However, surprisingly, we did not observe distinct gene expression signatures for the classical different WM lesion types, rather a continuum of change. This indicates that classical lesion characterization better reflects changes in cell abundance than changes in cell type gene expression, and indicates a global disease effect. Furthermore, the major biological determinants of variability in gene expression in MS WM samples relate to individual patient effects, rather than to lesion types or other metadata. We identify four subgroups of MS patients with distinct WM glial gene expression signatures and patterns of oligodendrocyte stress and/or maturation, suggestive of engagement of different pathological processes, with an additional more variable regenerative astrocyte signature. The discovery of these patterns, which were also found in an independent MS patient cohort, provides a framework to use molecular biomarkers to stratify patients for optimal therapeutic approaches for progressive MS, significantly advances our mechanistic understanding of progressive MS, and highlights the need for precision-medicine approaches to address heterogeneity among MS patients.

neuroscience↗

bioRxiv2019

PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS

Peripheral nervous system (PNS) neurons support axon regeneration into adulthood, whereas central nervous system (CNS) neurons lose regenerative ability after development. To better understand this decline whilst aiming to improve regeneration, we focused on phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol(3,4,5)-trisphosphate (PIP3). We found that neuronal PIP3 decreases with maturity in line with regenerative competence, firstly in the cell body and subsequently in the axon. We show that adult PNS neurons utilise two catalytic subunits of PI3K for efficient regeneration: p110 and p110{delta}. Overexpressing p110 in CNS neurons had no effect, however expression of p110{delta} restored axonal PIP3 and enhanced CNS regeneration in rat and human neurons and in transgenic mice, functioning in the same way as the hyperactivating H1047R mutation of p110. Furthermore, viral delivery of p110{delta} promoted robust regeneration after optic nerve injury. These findings demonstrate a deficit of axonal PIP3 as a reason for intrinsic regeneration failure and show that native p110{delta} facilitates axon regeneration by functioning in a hyperactive fashion.

neuroscience↗

bioRxiv2019

Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte-myelin dysfunction

Although the underlying neurobiology of major mental illness (MMI) remains unknown, emerging evidence implicates a role for oligodendrocyte-myelin abnormalities. Here, we took advantage of a large family carrying a balanced t(1;11) translocation, which substantially increases risk of MMI, to undertake both diffusion tensor imaging (DTI) and cellular studies to evaluate the consequences of the t(1;11) translocation on white matter structural integrity and oligodendrocyte-myelin biology. This translocation disrupts among others the DISC1 gene which plays a crucial role in brain development. We show that translocation-carrying patients display significant disruption in white matter integrity compared to familial controls. At a cellular level, we observe dysregulation of key pathways controlling oligodendrocyte development and morphogenesis in induced pluripotent stem cell (iPSC) case derived oligodendrocytes. This is associated with reduced proliferation and a stunted morphology in vitro. Further, myelin internodes in a humanized mouse model that recapitulates the human translocation as well as after transplantation of t(1;11) oligodendrocyte progenitors were significantly reduced compared to controls. Thus we provide evidence that the t(1;11) translocation has biological effects at both the systems and cellular level that together suggest oligodendrocyte-myelin dysfunction.

neuroscience↗