Dr David A Menassa | University of Oxford (original) (raw)

Papers by Dr David A Menassa

Acta Neuropathologica, Aug 31, 2023

Microglia are the brain's resident macrophages, which guide various developmental processes cruci... more Microglia are the brain's resident macrophages, which guide various developmental processes crucial for brain maturation, activity, and plasticity. Microglial progenitors enter the telencephalic wall by the 4th postconceptional week and colonise the fetal brain in a manner that spatiotemporally tracks key neurodevelopmental processes in humans. However, much of what we know about how microglia shape neurodevelopment comes from rodent studies. Multiple differences exist between human and rodent microglia warranting further focus on the human condition, particularly as microglia are emerging as critically involved in the pathological signature of various cognitive and neurodevelopmental disorders. In this article, we review the evidence supporting microglial involvement in basic neurodevelopmental processes by focusing on the human species. We next concur on the neuropathological evidence demonstrating whether and how microglia contribute to the aetiology of two neurodevelopmental disorders: autism spectrum conditions and schizophrenia. Next, we highlight how recent technologies have revolutionised our understanding of microglial biology with a focus on how these tools can help us elucidate at unprecedented resolution the links between microglia and neurodevelopmental disorders. We conclude by reviewing which current treatment approaches have shown most promise towards targeting microglia in neurodevelopmental disorders and suggest novel avenues for future consideration.

Calcitonin paracrine signaling controls heart fibrogenesis and arrhythmia

Journal of Molecular and Cellular Cardiology, Dec 1, 2022

Spatiotemporal dynamics of human microglia are linked with brain developmental processes across the lifespan

bioRxiv (Cold Spring Harbor Laboratory), Aug 7, 2021

Microglia, the brain’s resident macrophages, shape neural development and wiring, and are key neu... more Microglia, the brain’s resident macrophages, shape neural development and wiring, and are key neuroimmune hubs in the pathological signature of neurodevelopmental disorders. In the human brain, microglial development has not been carefully examined yet, and most of our knowledge derives from rodents. We established an unprecedented collection of 97 postmortem tissues enabling quantitative, sex-matched, detailed analysis of microglial across the human lifespan. We identify the dynamics of these cells in the human telencephalon, describing novel waves in microglial density across gestation and infancy, controlled by a balance of proliferation and apoptosis, which track key neurodevelopmental milestones. These profound changes in microglia are also observed in bulk RNAseq and single-cell RNAseq datasets. This study provides unparalleled insight and detail into the spatiotemporal dynamics of microglia across the human lifespan. Our findings serve as a solid foundation for elucidating how microglia contribute to shaping neurodevelopment in humans.

Acta Neuropathologica, 2023

Microglia colonize the developing brain by clonal expansion of highly proliferative progenitors, following allometric scaling

Cell Reports

Physiological Reports

This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Microglial Characterization in Transient Human Neurodevelopmental Structures

Developmental Neuroscience

Human neurodevelopment is characterized by the appearance, development, and disappearance or tran... more Human neurodevelopment is characterized by the appearance, development, and disappearance or transformation of various transient structures that underlie the establishment of connectivity within and between future cortical and subcortical areas. Examples of transient structures in the forebrain (among many others) include the subpial granular layer and the subplate zone. We have previously characterized the precise spatiotemporal dynamics of microglia in the human telencephalon. Here, we describe the diversity of microglial morphologies in the subpial granular layer and the subplate zone. Where possible, we couple the predominant morphological phenotype with functional characterizations to infer tentative roles for microglia in a changing neurodevelopmental landscape. We interpret these findings within the context of relevant morphogenetic and neurogenetic events in humans. Due to the unique genetic, molecular, and anatomical features of the human brain and because many human neurol...

Berridge 2018 Supplementary data

Supplementary Data Berridge et al submitted to Neurology. Glutamate receptor delta2 serum antibod... more Supplementary Data Berridge et al submitted to Neurology. Glutamate receptor delta2 serum antibodies in paediatric opsoclonus myoclonus ataxia syndrome. Data on proteins identified and clinical subjects who harbour autoantibodies to the protein Glutamate receptor delta

Magnetoencephalography and Neuropathological Studies of Autism Spectrum Disorders and the Comorbidity with Epilepsy

Additional file 3: Summed ADI-R domain scores for autism cases

Citations Michael E. Habicht

Nature, 2020

-Atrial fibrillation (AF), the most common cardiac arrhythmia, is a major contributor to populati... more -Atrial fibrillation (AF), the most common cardiac arrhythmia, is a major contributor to population mortality and morbidity, particularly stroke-risk. 1 Atrialtissue fibrosis is a central pathophysiological feature and hampers AF-treatment; the underlying molecular mechanisms are poorly understood and present therapies are inadequate. 2 Here, we show that calcitonin (CT), a well-recognized hormone product of the thyroid gland involved in bone metabolism, 3 is produced in significant quantities by atrial cardiomyocytes and acts in a paracrine fashion on neighbouring collagenproducing fibroblasts to control their proliferation and secretion of extracellular matrix proteins. Global disruption of CT-receptor signalling in mice causes atrial fibrosis and increases AF susceptibility. Atrial-specific knockdown (KD) of CT in atrial-targeted liver-kinase B1 (LKB1)-KD mice promotes atrial fibrosis and prolongs/increases the number of spontaneous AF-episodes, while atrial-specific CT overexpression prevents fibrosis and AF in LKB1-KD mice. Patients with persistent AF are characterised by six-3 fold reduction in myocardial CT levels and by loss of fibroblast membrane CT receptors. Transcriptome analysis of human atrial fibroblasts exposed to CT show little change, whereas proteomic analysis indicates extensive alterations in extracellularmatrix proteins and pathways related to fibrogenesis, infection/immune responses and transcriptional regulation. Strategies to restore disrupted myocardial CT signalling may offer new therapeutic avenues for patients with AF. Background-AF, the most prevalent cardiac arrhythmia, is associated with significant mortality and morbidity. AF-treatment is complicated by adverse atrial remodelling 2. Current pharmacological strategies for AF are non-specific and can produce adverse effects. The identification of novel pathophysiologically-related targets might open new therapeutic avenues 2. AF-related structural remodelling involves accumulation of cross-linked collagen from atrial cardiofibroblasts (ACFs). The underlying mechanisms are incompletely understood. Calcitonin (CT), produced by thyroid parafollicular cells, plays a well-known role in bone resorption and collagen turnover 3 , and affects other tissues like skeletal muscle. 4 Circulating CT-levels decrease with age 5 , the main risk-factor for AF. 1,2 Genome-wideassociation studies (GWAS) report links between single-nucleotide polymorphisms in the CT-receptor (CTR) and body mass index 6 , another AF risk-factor. CT prevents calciuminduced ventricular arrhythmias 7 and inhibits atrial chrono-/inotropic function 8. No information is available about CT-involvement in AF, nor regarding functional extrathyroid CT-production. Here, we sought to (i) assess whether atrial myocardium produces CT and identify the cellular source(s), (ii) explore paracrine CTR-mediated effects on ACF proliferation and 4 collagen processing and, (iii) determine whether CT-signalling regulates atrial fibrotic remodelling and AF-susceptibility. Results Atrial cardiomyocytes produce CT. Atrial myocardium secretes several hormones 9. We investigated CT gene-expression in human right-atrial tissue, isolated atrial cardiomyocytes (ACMs), ACFs and epicardial fat (detailed in Extended Data Table 1). Human CT originates from the calcitonin-related polypeptide-alpha (CALCA) gene on chromosome-11 (ID:ENSG00000110680), co-transcribed into alpha-calcitonin gene-related peptide (αCGRP). CT and αCGRP transcripts were detected in human atrium, isolated ACMs and ACFs, but not adipose tissue (Fig.1a-c). CT-protein was apparent in the secretome of human ACMs, but not ACFs (Fig.1d). Persistent-AF patients had impaired ability to produce mature CT and its precursor pro-CT (Fig.1e-g), mirrored by increased αCGRP-protein in human right-atrial tissue-lysates and ACM-secretome (Extended Data Fig.1a-b). ACM-CT and αCGRP mRNA-expression and CT/αCGRP ratio were unchanged in AF (Extended Data Fig.1c-e); ACM-CT correlated negatively with age (Extended Data Fig.1f). We then compared CTgene expression and secretion between human ACMs and TT-cells (which constitutively produce large amounts of CT) from a 77-year old with medullary thyroid carcinoma. CT gene-expression in ACMs was ~half that of TT-cells (Fig.1h); ACM CT-secretion was ~16fold greater than TT-cells (Fig.1i). Thus, human ACMs are an active source of extrathyroid CT. Human ACFs express functional CTRs. CT exerts its biological actions via the CTR. Human atrial myocardium exclusively expresses the most abundant 1a-isoform of the CTR (Extended Data Fig.1g-h). Similarly, CTRs are expressed in ACFs (by qPCR, immunoblotting and immunostaining; Fig.1j-k, Extended Data Fig.1i).

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, Jan 22, 2018

St. Catherine of Siena suffered from an extreme form of holy fasting, a condition classified as a... more St. Catherine of Siena suffered from an extreme form of holy fasting, a condition classified as anorexia mirabilis (also known as inedia prodigiosa). Historical and medical scholarships alike have drawn a comparison between this primaeval type of anorexia with a relatively common form of eating disorder among young women in the modern world, anorexia nervosa. St. Catherine's condition was characterised by a disgust for sweet taste, a condition also described in anorexia nervosa, and characterised by specific neurophysiological changes in the brain. St. Catherine's case may be considered one of the oldest veritable descriptions of altered gustation (dysgeusia). Moreover, a more compelling neurophysiological similarity between anorexia mirabilis and anorexia nervosa may be proposed.

Neuron, 2018

Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with ne... more Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer ...

PLOS ONE, 2017

Background Cycle use across London and the UK has increased considerably over the last 10 years. ... more Background Cycle use across London and the UK has increased considerably over the last 10 years. With this there has been an increased interest in cycle safety and injury prevention. Head injuries are an important cause of mortality and morbidity in cyclists. This study aimed to ascertain the frequency of different head injury types in cyclists and whether wearing a bicycle helmet affords protection against specific types of head injury. Methods A retrospective observational study of all cyclists older than 16 years admitted to a London Major Trauma Centre between 1 st January 2011 and 31 st December 2015 was completed. A cohort of patients who had serious head injury was identified (n = 129). Of these, data on helmet use was available for 97. Comparison was made between type of injury frequency in helmeted and non-helmeted cyclists within this group of patients who suffered serious head injury.

Effects of heat acclimation on heat shock protein 72 and cytokine response to job-related exercise whilst wearing bomb disposal suit in temperate and hot conditions

Developmental Cell

Highlights d A roadmap of microglial dynamics across the human lifespan d The density of microgli... more Highlights d A roadmap of microglial dynamics across the human lifespan d The density of microglial cells follows a wave-like pattern during development d Microglial fluctuations are spatiotemporally linked to key neurodevelopmental hallmarks

Data from: Glutamate receptor delta2 serum antibodies in paediatric opsoclonus myoclonus ataxia syndrome

Objective: To identify neuronal surface antibodies in opsoclonus myoclonus ataxia syndrome (OMAS)... more Objective: To identify neuronal surface antibodies in opsoclonus myoclonus ataxia syndrome (OMAS) usingcontemporary antigen discovery methodology. Methods: OMAS patient serum IgG immunohistochemistry using age-equivalent rat cerebellar tissue was followed by immunoprecipitation, gel electrophoresis and mass spectrometry. Data are available via ProteomeXchange (identifier PXD009578). This generated a list of potential neuronal surface cerebellar autoantigens. Live cell-based assays (CBA) were used to confirm membrane-surface antigens and adsorb antigen-specific IgGs. The serological results were compared to the clinical data. Results: Four of the six OMAS sera tested bound rat cerebellar sections. Two of these sera with similar immunoreactivities were used in immunoprecipitation experiments using cerebellum from postnatal rat pups (P18). Mass spectrometry identified 12 cell-surface proteins, of which glutamate receptor delta 2 (GluD2), a predominately cerebellar-expressed protein, was found at a threefold higher concentration than the other 11 proteins. Antibodies to GluD2 were identified in 14/16 (87%) OMAS samples, compared with 5/139 (5%) pediatric and 1/38 (2.6%) adult serum controls (p<0.0001), and in 2/4 sera from patients with neuroblastoma without neurological features. Adsorption of positive OMAS sera against GluD2-transfected cells substantially reduced but did not eliminate, reactivity towards cerebellar sections. Conclusion: Autoantibodies to GluD2 are frequent in patients with OMAS, bind to surface determinants and are potentially pathogenic

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