Publications
74 results found
Brockman E, De Paola V, 2022, Say Cheese! Snapshots of the Living Mouse Brain, Frontiers for Young Minds, Vol: 10
<jats:p>The human brain is a highly complex system comprised of billions of cells, called neurons, that are all interconnected. Normal brain function depends on effective communication between neurons, which requires signals to travel down a nerve cell and then over to the next cell it is connected to. Several diseases result from impairments in the communication between neurons, which is why it is important to study these signals in the living brain. Since the living human brain is difficult to study, scientists use simpler organisms like mice. To see mouse neurons, a piece of skull is replaced with a clear glass window. Powerful microscopes can then be used to capture snapshots of neurons deep inside live brains! Clever use of lasers to excite chemical “tags” inside the neurons makes them glow with fluorescent light. Join us as we explore the inner workings of neuron communication in the living brain.</jats:p>
Calderon L, Weiss FD, Beagan JA, et al., 2022, Cohesin-dependence of neuronal gene expression relates to chromatin loop length, eLife, Vol: 11, ISSN: 2050-084X
Cohesin and CTCF are major drivers of 3D genome organization, but their role in neurons is still emerging. Here, we show a prominent role for cohesin in the expression of genes that facilitate neuronal maturation and homeostasis. Unexpectedly, we observed two major classes of activity-regulated genes with distinct reliance on cohesin in mouse primary cortical neurons. Immediate early genes (IEGs) remained fully inducible by KCl and BDNF, and short-range enhancer-promoter contacts at the IEGs Fos formed robustly in the absence of cohesin. In contrast, cohesin was required for full expression of a subset of secondary response genes characterized by long-range chromatin contacts. Cohesin-dependence of constitutive neuronal genes with key functions in synaptic transmission and neurotransmitter signaling also scaled with chromatin loop length. Our data demonstrate that key genes required for the maturation and activation of primary cortical neurons depend on cohesin for their full expression, and that the degree to which these genes rely on cohesin scales with the genomic distance traversed by their chromatin contacts.Editor's
Davis N, Mota BC, Stead L, et al., 2021, Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer's disease, Journal of Neuroinflammation, Vol: 18, ISSN: 1742-2094
BackgroundAstrocytes provide a vital support to neurons in normal and pathological conditions. In Alzheimer’s disease (AD) brains, reactive astrocytes have been found surrounding amyloid plaques, forming an astrocytic scar. However, their role and potential mechanisms whereby they affect neuroinflammation, amyloid pathology, and synaptic density in AD remain unclear.MethodsTo explore the role of astrocytes on Aβ pathology and neuroinflammatory markers, we pharmacologically ablated them in organotypic brain culture slices (OBCSs) from 5XFAD mouse model of AD and wild-type (WT) littermates with the selective astrocytic toxin L-alpha-aminoadipate (L-AAA). To examine the effects on synaptic circuitry, we measured dendritic spine number and size in OBCSs from Thy-1-GFP transgenic mice incubated with synthetic Aβ42 or double transgenics Thy-1-GFP/5XFAD mice treated with LAAA or vehicle for 24 h.ResultsTreatment of OBCSs with L-AAA resulted in an increased expression of pro-inflammatory cytokine IL-6 in conditioned media of WTs and 5XFAD slices, associated with changes in microglia morphology but not in density. The profile of inflammatory markers following astrocytic loss was different in WT and transgenic cultures, showing reductions in inflammatory mediators produced in astrocytes only in WT sections. In addition, pharmacological ablation of astrocytes led to an increase in Aβ levels in homogenates of OBCS from 5XFAD mice compared with vehicle controls, with reduced enzymatic degradation of Aβ due to lower neprilysin and insulin-degrading enzyme (IDE) expression. Furthermore, OBSCs from wild-type mice treated with L-AAA and synthetic amyloid presented 56% higher levels of Aβ in culture media compared to sections treated with Aβ alone, concomitant with reduced expression of IDE in culture medium, suggesting that astrocytes contribute to Aβ clearance and degradation. Quantification of hippocampal dendritic spines revealed a reducti
Calderon L, Weiss FD, Beagan JA, et al., 2021, Reliance of neuronal gene expression on cohesin scales with chromatin loop length
<jats:title>Abstract</jats:title><jats:p>Cohesin and CTCF are major drivers of 3D genome organization, but their role in neurons is still emerging. Here we show a prominent role for cohesin in the expression of genes that facilitate neuronal maturation and homeostasis. Unexpectedly, we observed two major classes of activity-regulated genes with distinct reliance on cohesin in primary cortical neurons. Immediate early genes remained fully inducible by KCl and BDNF, and short-range enhancer-promoter contacts at the Immediate early gene <jats:italic>Fos</jats:italic> formed robustly in the absence of cohesin. In contrast, cohesin was required for full expression of a subset of secondary response genes characterised by long-range chromatin contacts. Cohesin-dependence of constitutive neuronal genes with key functions in synaptic transmission and neurotransmitter signaling also scaled with chromatin loop length. Our data demonstrate that key genes required for the maturation and activation of primary cortical neurons depend cohesin for their full expression, and that the degree to which these genes rely on cohesin scales with the genomic distance traversed by their chromatin contacts.</jats:p>
Canty AJ, Jackson JS, Huang L, et al., 2020, In vivo imaging of injured cortical axons reveals a rapid onset form of Wallerian degeneration, BMC Biology, Vol: 18
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Despite the widespread occurrence of axon and synaptic loss in the injured and diseased nervous system, the cellular and molecular mechanisms of these key degenerative processes remain incompletely understood. Wallerian degeneration (WD) is a tightly regulated form of axon loss after injury, which has been intensively studied in large myelinated fibre tracts of the spinal cord, optic nerve and peripheral nervous system (PNS). Fewer studies, however, have focused on WD in the complex neuronal circuits of the mammalian brain, and these were mainly based on conventional endpoint histological methods. Post-mortem analysis, however, cannot capture the exact sequence of events nor can it evaluate the influence of elaborated arborisation and synaptic architecture on the degeneration process, due to the non-synchronous and variable nature of WD across individual axons.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>To gain a comprehensive picture of the spatiotemporal dynamics and synaptic mechanisms of WD in the nervous system, we identify the factors that regulate WD within the mouse cerebral cortex. We combined single-axon-resolution multiphoton imaging with laser microsurgery through a cranial window and a fluorescent membrane reporter. Longitudinal imaging of > 150 individually injured excitatory cortical axons revealed a threshold length below which injured axons consistently underwent a rapid-onset form of WD (roWD). roWD started on average 20 times earlier and was executed 3 times slower than WD described in other regions of the nervous system. Cortical axon WD and roWD were dependent on synaptic density, but independent of axon complexity. Finally, pharmacological and genetic manipulations showed t
Davis N, Mota B, Stead L, et al., 2020, Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer’s disease, Publisher: BioMed Central
Canty A, Jackson J, Huang L, et al., 2020, In vivo imaging of injured cortical axons reveals a rapid onset form of Wallerian degeneration, BMC Biology, ISSN: 1741-7007
Background Despite the widespread occurrence of axon and synaptic loss in the injured and diseased nervous system, the cellular and molecular mechanisms of these key degenerative processes remain incompletely understood. Wallerian degeneration (WD) is a tightly regulated form of axon loss after injury, which has been intensively studied in large myelinated fibre tracts of the spinal cord, optic nerve and peripheral nervous system (PNS). Fewer studies, however, have focused on WD in the complex neuronal circuits of the mammalian brain, and these were mainly based on conventional endpoint histological methods. Post-mortem analysis, however, cannot capture the exact sequence of events nor can it evaluate the influence of elaborated arborization and synaptic architecture on the degeneration process, due to the non-synchronous and variable nature of WD across individual axons. Results To gain a comprehensive picture of the spatiotemporal dynamics and synaptic mechanisms of WD in the nervous system, we identify the factors that regulate WD within the mouse cerebral cortex. We combined single-axon-resolution multiphoton imaging with laser microsurgery through a cranial window and a fluorescent membrane reporter. Longitudinal imaging of > 150 individually injured excitatory cortical axons revealed a threshold length below which injured axons consistently underwent a rapid-onset form of WD (roWD). roWD started 10 times earlier and was executed 4 times slower than WD described in other regions of the nervous system. Cortical axon WD and roWD were dependent on synaptic density, but independent of axon complexity. Finally, pharmacological and genetic manipulations showed that a Nicotinamide Adenine Dinucleotide (NAD+)-dependent pathway could delay cortical roWD independent of transcription in the damaged neurons, demonstrating further conservation of the molecular mechanisms controlling WD in different areas of the mammalian nervous system. Conclusions Our data highlight the
Calderon L, Weiss FD, Carroll T, et al., 2019, Cohesin is continuously required to sustain neuronal gene expression, 29th Mammalian Genetics and Development Workshop of the Genetics-Society, Publisher: HINDAWI LTD, ISSN: 0016-6723
Real R, Peter M, Trabalza A, et al., 2018, In vivo modeling of human neuron dynamics and Down syndrome., Science, Vol: 362
Harnessing the potential of human stem cells for modeling the physiology and diseases of cortical circuitry requires monitoring cellular dynamics in vivo. We show that human induced pluripotent stem cell (iPSC)-derived cortical neurons transplanted into the adult mouse cortex consistently organized into large (up to ~100 mm3) vascularized neuron-glia territories with complex cytoarchitecture. Longitudinal imaging of >4000 grafted developing human neurons revealed that neuronal arbors refined via branch-specific retraction; human synaptic networks substantially restructured over 4 months, with balanced rates of synapse formation and elimination; and oscillatory population activity mirrored the patterns of fetal neural networks. Lastly, we found increased synaptic stability and reduced oscillations in transplants from two individuals with Down syndrome, demonstrating the potential of in vivo imaging in human tissue grafts for patient-specific modeling of cortical development, physiology, and pathogenesis.
Bloomfield PS, Bonsall D, Wells L, et al., 2018, The effects of haloperidol on microglial morphology and translocator protein levels: An in vivo study in rats using an automated cell evaluation pipeline, Journal of Psychopharmacology, Vol: 32, Pages: 1264-1272, ISSN: 1461-7285
BACKGROUND: Altered microglial markers and morphology have been demonstrated in patients with schizophrenia in post-mortem and in vivo studies. However, it is unclear if changes are due to antipsychotic treatment. AIMS: Here we aimed to determine whether antipsychotic medication affects microglia in vivo. METHODS: To investigate this we administered two clinically relevant doses (0.05 mg n=12 and 2.5 mg n=7 slow-release pellets, placebo n=20) of haloperidol, over 2 weeks, to male Sprague Dawley rats to determine the effect on microglial cell density and morphology (area occupied by processes and microglial cell area). We developed an analysis pipeline for the automated assessment of microglial cells and used lipopolysaccharide (LPS) treatment ( n=13) as a positive control for analysis. We also investigated the effects of haloperidol ( n=9) or placebo ( n=10) on the expression of the translocator protein 18 kDa (TSPO) using autoradiography with [3H]PBR28, a TSPO ligand used in human positron emission tomography (PET) studies. RESULTS: Here we demonstrated that haloperidol at either dose does not alter microglial measures compared with placebo control animals ( p > 0.05). Similarly there was no difference in [3H]PBR28 binding between placebo and haloperidol tissue ( p > 0.05). In contrast, LPS was associated with greater cell density ( p = 0.04) and larger cell size ( p = 0.01). CONCLUSION: These findings suggest that haloperidol does not affect microglial cell density, morphology or TSPO expression, indicating that clinical study alterations are likely not the consequence of antipsychotic treatment. The automated cell evaluation pipeline was able to detect changes in microglial morphology induced by LPS and is made freely available for future use.
Calì C, Wawrzyniak M, Becker C, et al., 2018, The effects of aging on neuropil structure in mouse somatosensory cortex-A 3D electron microscopy analysis of layer 1, PLoS ONE, Vol: 13, ISSN: 1932-6203
This study has used dense reconstructions from serial EM images to compare the neuropil ultrastructure and connectivity of aged and adult mice. The analysis used models of axons, dendrites, and their synaptic connections, reconstructed from volumes of neuropil imaged in layer 1 of the somatosensory cortex. This shows the changes to neuropil structure that accompany a general loss of synapses in a well-defined brain region. The loss of excitatory synapses was balanced by an increase in their size such that the total amount of synaptic surface, per unit length of axon, and per unit volume of neuropil, stayed the same. There was also a greater reduction of inhibitory synapses than excitatory, particularly those found on dendritic spines, resulting in an increase in the excitatory/inhibitory balance. The close correlations, that exist in young and adult neurons, between spine volume, bouton volume, synaptic size, and docked vesicle numbers are all preserved during aging. These comparisons display features that indicate a reduced plasticity of cortical circuits, with fewer, more transient, connections, but nevertheless an enhancement of the remaining connectivity that compensates for a generalized synapse loss.
Akassoglou K, Merlini M, Rafalski VA, et al., 2017, In Vivo Imaging of CNS Injury and Disease, Journal of Neuroscience, Vol: 37, Pages: 10808-10816, ISSN: 0270-6474
In vivo optical imaging has emerged as a powerful tool with which to study cellular responses to injury and disease in the mammalian CNS. Important new insights have emerged regarding axonal degeneration and regeneration, glial responses and neuroinflammation, changes in the neurovascular unit, and, more recently, neural transplantations. Accompanying a 2017 SfN Mini-Symposium, here, we discuss selected recent advances in understanding the neuronal, glial, and other cellular responses to CNS injury and disease with in vivo imaging of the rodent brain or spinal cord. We anticipate that in vivo optical imaging will continue to be at the forefront of breakthrough discoveries of fundamental mechanisms and therapies for CNS injury and disease.
Bass C, Helkkula P, De Paola V, et al., 2017, Detection of axonal synapses in 3D two-photon images, PLoS One, Vol: 12, Pages: 1-18, ISSN: 1932-6203
Studies of structural plasticity in the brain often require the detection and analysis of axonal synapses (boutons). To date, bouton detection has been largely manual or semi-automated, relying on a step that traces the axons before detection the boutons. If tracing the axon fails, the accuracy of bouton detection is compromised. In this paper, we propose a new algorithm that does not require tracing the axon to detect axonal boutons in 3D two-photon images taken from the mouse cortex. To find the most appropriate techniques for this task, we compared several well-known algorithms for interest point detection and feature descriptor generation. The final algorithm proposed has the following main steps: (1) a Laplacian of Gaussian (LoG) based feature enhancement module to accentuate the appearance of boutons; (2) a Speeded Up Robust Features (SURF) interest point detector to find candidate locations for feature extraction; (3) non-maximum suppression to eliminate candidates that were detected more than once in the same local region; (4) generation of feature descriptors based on Gabor filters; (5) a Support Vector Machine (SVM) classifier, trained on features from labelled data, and was used to distinguish between bouton and non-bouton candidates. We found that our method achieved a Recall of 95%, Precision of 76%, and F1 score of 84% within a new dataset that we make available for accessing bouton detection. On average, Recall and F1 score were significantly better than the current state-of-the-art method, while Precision was not significantly different. In conclusion, in this article we demonstrate that our approach, which is independent of axon tracing, can detect boutons to a high level of accuracy, and improves on the detection performance of existing approaches. The data and code (with an easy to use GUI) used in this article are available from open source repositories.
French PMW, Görlitz F, Kelly D, et al., 2017, Open source high content analysis utilizing automated fluorescence lifetime imaging microscopy, Jove-Journal of Visualized Experiments, Vol: 119, ISSN: 1940-087X
We present an open source high content analysis instrument utilizing automated fluorescence lifetime imaging (FLIM) for assaying protein interactions using Förster resonance energy transfer (FRET) based readouts of fixed or live cells in multiwell plates. This provides a means to screen for cell signaling processes read out using intramolecular FRET biosensors or intermolecular FRET of protein interactions such as oligomerization or heterodimerization, which can be used to identify binding partners. We describe herethe functionality of this automated multiwell plate FLIM instrumentation and present exemplar data from our studies of HIV Gag protein oligomerization and a time course of a FRET biosensor in live cells. A detailed description of the practical implementation is then provided with reference to a list of hardware components and a description of the open source data acquisition software written in μ Manager. The application of FLIMfit, an open source MATLAB-based client for the OMERO platform, to analyze arrays of multiwell plate FLIM data is also presented. The protocols for imaging fixed and live cells are outlined and a demonstration of an automated multiwell plate FLIM experiment using cells expressing fluorescent protein-based FRET constructs is presented. This is complemented by a walk-through of the data analysis for this specific FLIM FRET data set.
Krusche B, Ottone C, Clements MP, et al., 2016, EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells, eLife, Vol: 5, ISSN: 2050-084X
Glioblastomas (GBM) are aggressive and therapy-resistant brain tumours, which contain a subpopulation of tumour-propagating glioblastoma stem-like cells (GSC) thought to drive progression and recurrence. Diffuse invasion of the brain parenchyma, including along preexisting blood vessels, is a leading cause of therapeutic resistance, but the mechanisms remain unclear. Here, we show that ephrin-B2 mediates GSC perivascular invasion. Intravital imaging, coupled with mechanistic studies in murine GBM models and patient-derived GSC, revealed that endothelial ephrin-B2 compartmentalises non-tumourigenic cells. In contrast, upregulation of the same ephrin-B2 ligand in GSC enabled perivascular migration through homotypic forward signalling. Surprisingly, ephrin-B2 reverse signalling also promoted tumourigenesis cell-autonomously, by mediating anchorage-independent cytokinesis via RhoA. In human GSC-derived orthotopic xenografts, EFNB2 knock-down blocked tumour initiation and treatment of established tumours with ephrin-B2-blocking antibodies suppressed progression. Thus, our results indicate that targeting ephrin-B2 may be an effective strategy for the simultaneous inhibition of invasion and proliferation in GBM.
Bloomfield P, Sudhakar S, Veronese V, et al., 2016, Microglial activity in people at ultra high risk of psychosis and in schizophrenia; an [11C]PBR28 PET brain imaging study, American Journal of Psychiatry, Vol: 173, Pages: 44-52, ISSN: 0002-953X
Objective:The purpose of this study was to determine whether microglial activity, measured using translocator-protein positron emission tomography (PET) imaging, is increased in unmedicated persons presenting with subclinical symptoms indicating that they are at ultra high risk of psychosis and to determine whether microglial activity is elevated in schizophrenia after controlling for a translocator-specific genetic polymorphism.Method:The authors used the second-generation radioligand [11C]PBR28 and PET to image microglial activity in the brains of participants at ultra high risk for psychosis. Participants were recruited from early intervention centers. The authors also imaged a cohort of patients with schizophrenia and matched healthy subjects for comparison. In total, 56 individuals completed the study. At screening, participants were genotyped to account for the rs6971 polymorphism in the gene encoding the 18Kd translocator protein. The main outcome measure was total gray matter [11C]PBR28 binding ratio, representing microglial activity.Results:[11C]PBR28 binding ratio in gray matter was elevated in ultra-high-risk participants compared with matched comparison subjects (Cohen’s d >1.2) and was positively correlated with symptom severity (r=0.730). Patients with schizophrenia also demonstrated elevated microglial activity relative to matched comparison subjects (Cohen’s d >1.7).Conclusions:Microglial activity is elevated in patients with schizophrenia and in persons with subclinical symptoms who are at ultra high risk of psychosis and is related to at-risk symptom severity. These findings suggest that neuroinflammation is linked to the risk of psychosis and related disorders, as well as the expression of subclinical symptoms.
Grillo F, Canty AJ, Bloomfield P, et al., 2015, 2015, In vivo visualization of single axons and synaptic remodeling in normal and pathological conditions, Publisher: Axons and Brain Architecture, Elsevier 2015, ISBN: 9780128013939
Selvaraj S, Bloomfield P, Veronese M, et al., 2015, Imaging Translocator Protein (TSPO) in subjects at high risk of psychosis and in schizophrenia: An [11C] PBR28 pet brain imaging study, 54th Annual Meeting of the American-College-of-Neuropsychopharmacology (ACNP), Publisher: Nature Publishing Group, Pages: S559-S560, ISSN: 0893-133X
Jackson J, Canty AJ, Huang L, et al., 2015, Laser-Mediated Microlesions in Mouse Neocortex to Investigate Neuronal Degeneration and Regeneration., Curr Protoc Neurosci, Vol: 73, Pages: 2.24.1-2.24.17
In vivo two-photon (2P) imaging enables neural circuitry to be repeatedly visualized in both normal conditions and following trauma. This protocol describes how laser-mediated neuronal microlesions can be created in the cerebral cortex using an ultrafast laser without causing a significant inflammatory reaction or compromising the blood-brain barrier. Furthermore, directives are provided for the acute and chronic in vivo imaging of the lesion site, as well as for post-hoc analysis of the lesion site in fixed tissue, which can be correlated with the live imaging phase.
Ilse S Pienaar, Sarah E Gartside, Puneet Sharma, et al., 2015, Pharmacogenetic stimulation of cholinergic pedunculopontine neurons reverses motor deficits in a rat model of Parkinson’s disease, Molecular Neurodegeneration, Vol: 10, ISSN: 1750-1326
Background: Patients with advanced Parkinson's disease (PD) often present with axial symptoms, includingpostural- and gait difficulties that respond poorly to dopaminergic agents. Although deep brain stimulation (DBS) ofa highly heterogeneous brain structure, the pedunculopontine nucleus (PPN), improves such symptoms, theunderlying neuronal substrate responsible for the clinical benefits remains largely unknown, thus hamperingoptimization of DBS interventions. Choline acetyltransferase (ChAT)::Cre+ transgenic rats were sham-lesioned orrendered parkinsonian through intranigral, unihemispheric stereotaxic administration of the ubiquitin-proteasomalsystem inhibitor, lactacystin, combined with designer receptors exclusively activated by designer drugs (DREADD),to activate the cholinergic neurons of the nucleus tegmenti pedunculopontine (PPTg), the rat equivalent of thehuman PPN. We have previously shown that the lactacystin rat model accurately reflects aspects of PD, including apartial loss of PPTg cholinergic neurons, similar to what is seen in the post-mortem brains of advanced PD patients.Results: In this manuscript, we show that transient activation of the remaining PPTg cholinergic neurons in thelactacystin rat model of PD, via peripheral administration of the cognate DREADD ligand, clozapine-N-oxide (CNO),dramatically improved motor symptoms, as was assessed by behavioral tests that measured postural instability, gait,sensorimotor integration, forelimb akinesia and general motor activity. In vivo electrophysiological recordingsrevealed increased spiking activity of PPTg putative cholinergic neurons during CNO-induced activation. c-Fosexpression in DREADD overexpressed ChAT-immunopositive (ChAT+) neurons of the PPTg was also increased byCNO administration, consistent with upregulated neuronal activation in this defined neuronal population.Conclusions: Overall, these findings provide evidence that functional modulation of PPN cholinergic neuronsalleviates parkinson
Bloomfield P, Selvaraj S, Bonoldi I, et al., 2015, Translational investigation of microglia and antipsychotic medication, GLIA, Vol: 63, Pages: E315-E315, ISSN: 0894-1491
Grillo FW, West L, De Paola V, 2015, Removing synaptic breaks on learning, Nature Neuroscience, Vol: 18, Pages: 1062-1064, ISSN: 1546-1726
Song S, Grillo F, Wang Q, et al., 2015, EPBscore: a novel method for computer-assisted analysis of axonal structure and dynamics, Neuroinformatics, Vol: 14, Pages: 121-127, ISSN: 1539-2791
Jackson J, Canty AJ, Huang L, et al., 2015, 2015, Laser mediated microlesions in the mouse neocortex to investigate neuronal degeneration and regeneration, Current Protocols in Neuroscience, ISSN: 1934-8584
Selvaraj S, Bloomfield P, Veronese M, et al., 2015, Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [11C]PBR28 PET Brain Imaging Study, BIOLOGICAL PSYCHIATRY, Vol: 77, ISSN: 0006-3223
Selvaraj S, Bonoldi I, Veronese M, et al., 2015, Microglia, psychosis and medication; a translational investigation. (De Paola and Howes, Co-Senior authors), BAP 2015 Summer Meeting (Selected for oral presentation)
Bloomfield P, Howes OD, De Paola V, 2015, THE EFFECTS OF ANTIPSYCHOTIC TREATMENT ON BRAIN VOLUME, INFLAMMATION AND GLUTAMATE SIGNALING GENES., SCHIZOPHRENIA BULLETIN, Vol: 41, Pages: S1-S1, ISSN: 0586-7614
Johnson MR, Behmoaras J, Bottolo L, et al., 2015, Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus, Nature Communications, Vol: 6, ISSN: 2041-1723
Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease. Here we employ systems genetics approaches to characterize the genetic regulation of pathophysiological pathways in human temporal lobe epilepsy (TLE). Using surgically acquired hippocampi from 129 TLE patients, we identify a gene-regulatory network genetically associated with epilepsy that contains a specialized, highly expressed transcriptional module encoding proconvulsive cytokines and Toll-like receptor signalling genes. RNA sequencing analysis in a mouse model of TLE using 100 epileptic and 100 control hippocampi shows the proconvulsive module is preserved across-species, specific to the epileptic hippocampus and upregulated in chronic epilepsy. In the TLE patients, we map the trans-acting genetic control of this proconvulsive module to Sestrin 3 (SESN3), and demonstrate that SESN3 positively regulates the module in macrophages, microglia and neurons. Morpholino-mediated Sesn3 knockdown in zebrafish confirms the regulation of the transcriptional module, and attenuates chemically induced behavioural seizures in vivo.
Pienaar I, Sharma P, Elson JL, et al., 2014, A DREADD approach for acute stimulation of cholinergic neurons of the pedunculopontine nucleus reverses Parkinsonism in the lactacystin model of Parkinson's disease (2014), Movement Disorders, Vol: 2014;29 Suppl 1 :381, ISSN: 1531-8257
Bloomfield PS, West L, Howes OD, et al., 2014, The effects of antipsychotic medication on cortical and peripheral inflammation. (*joint senior authors and corresponding authors), European Neuropsychopharmacology, Vol: 24, Pages: s516-s516, ISSN: 1873-7862
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