298 research outputs found
British Heart Rhythm Society Standards for Implantation and Follow-up of Cardiac Rhythm Management Devices in Adults: January 2024 Update.
No full textCopyright: © The Author(s) 2024. This work is open access and is licensed under CC BY-NC 4.0. Users may copy, redistribute and make derivative works for
non-commercial purposes, provided the original work is cited correctlyThis updated guidance is designed to help with implantation and follow-up with agreed standards of practice. The update includes new guidance on subcutaneous defibrillators, leadless pacemakers and conduction system pacing. It includes new guidance on considerations at the time of a potential box change and techniques to be considered to minimise the risk of infection
The role of the schizophrenia risk gene DiGeorge Critical Region 2 in projection neuron maturation in the medial prefrontal cortex
No full textSchizophrenia spectrum disorders have been linked to developmental alterations in the migration, maturation and function of projection neurons in brain regions such as the human dorsolateral prefrontal cortex. To explain these defects, many candidate risk genes have been proposed, some of which belonging to the 22q11.2DS region. This is the case of DGCR2, a schizophrenia risk gene previously shown in the lab to control the migration of superficial layer neocortical projection neurons.
For this thesis, we focused on the implication of Dgcr2 in the post-natal maturation of projection neurons dendritic spines. In this purpose, we performed a morphological analysis of spines coming from mice brains which underwent knock-down of Dgcr2 expression specifically in projection neurons during their development. We noticed a globally more immature dendritic spine profile in the Dgcr2 knock-down condition, a result compatible with previous findings in schizophrenia.
As a second aim, we also analysed results from a new genetic transfection method: in utero electroporation using a triple-electrode probe. We tested if this approach allows us to target efficiently, selectively and bilaterally a murine brain region called medial prefrontal cortex. This latter is known for its strong anatomical and functional homologies with the human dorsolateral prefrontal cortex. We showed that this technique presents a lot of advantages in comparison with its previous version using two electrodes, but also some limitations. We also identified some parameters in the procedure we have to improve in order to create a valid murine behavioural model of a medial prefrontal Dgcr2 knock-down alteration. </p
Impact of early-life serotonin dysregulation on cortical interneuron development
No full textEarly-life deficiency of the serotonin transporter (SERT) gives rise to a wide range of psychiatric-relevant phenotypes. Among the targets of early-life serotonin, the serotonin receptor 3A (5-HT3AR) specifically controls the embryonic migration and postnatal cortical laminar positioning of caudal ganglionic eminence (CGE) derived cortical interneurons (cINs). Here we investigated the impact of early-life SERT deficiency on the migration and positioning of CGE-derived cortical INs in SERT-ko mice and in mice exposed to the SERT inhibitor fluoxetine during the late embryonic period using microarray-based expression analysis and confocal imaging. We further aimed to identify the genetic programs that control the diversity of 5-HT3AR-expressing interneurons using single-cell RNA sequencing. Postnatal studies revealed that SERT-deficiency affects the cortical laminar distribution of specific CGE-derived interneuron. Preliminary single-cell results indicate that the combinatorial expression of transcription factors Nr2f2 and Sp8 may be a promising method to start re-classifying 5-HT3AR-expressing IN subtypes into biologically relevant subgroups
The role of DiGeorge Critical Region 2 in cortical circuit formation
No full textThe generation, migration and integration of different subtypes of neurons in cortical circuits has emerged as a key process in the pathophysiology of a variety of developmental disorders including autism spectrum disorders (ASD) and schizophrenia (SZ). Historical candidate-gene studies, as well as recent genome-wide association studies identified numerous genetic loci associated with schizophrenia. Many of these risk genes regulate embryonic cellular events involved in the formation of neural circuits. However, the functional role that schizophrenia-risk genes plays in the development of the disease is still largely unknown. During my PhD, I investigated the impact of a novel risk gene for schizophrenia, Di-George Critical Region 2 (Dgcr2) on cortical circuit formation. Dgcr2 is expressed throughout brain development and encodes for an activity-dependent adhesion protein. This gene is located in the 22q11.2 locus, in the minimal critical region that produces - when heterozygously deleted in humans - the 22q11 micro-deletion syndrome, also known as Di-George syndrome. This genetic micro-deletion is one of the highest known risk factors for schizophrenia, and DGCR2 has been highlighted as an important susceptibility gene from this locus, conferring increased risk for schizophrenia to 22q11 micro-deletion carriers. Additionally, exome sequencing of idiopathic schizophrenia family trios identified a rare de novo mutation in DGCR2 strongly associated with the disease, supporting the idea that DGCR2 is an important schizophrenia risk gene per se. However, evidence is still lacking about the function of DGCR2 in the pathophysiology of the disease. Here I aimed to describe the molecular mechanisms by which Dgcr2 impacts the construction of cortical microcircuits. In order to generate a developmental mouse model for schizophrenia, I performed in utero electroporation targeted to upper-layer pyramidal neurons (PN) and assessed the consequences of the shRNA-mediated Knock-Down (KD) of Dgcr2 on different steps of cortical circuit formation such as the proliferation of neuronal progenitors, neuronal migration and dendritogenesis. KD of the expression of mouse (m)Dgcr2 affected the laminar positioning of PN in a persistent manner in the somatosensory cortex. PN mispositioning due to Dgcr2 KD could be fully rescued by overexpressing the shRNA-resistant human (h)DGCR2 but not the (h)DGCR2 containing the SZ-risk mutation P429R, indicating a deleterious impact of this SZ-risk mutation on the migratory function of DGCR2. Surprisingly, I discovered that the P429R mutation is associated to a drastic reduction in the protein concentration of DGCR2, thus leading to a state of Dgcr2 haplo-insufficiency in a similar fashion as in the 22q11.2 microdeletion syndrome. Live-imaging techniques revealed that Dgcr2 KD significantly affected the dynamic locomotion of PN, indicating that Dgcr2 is likely to regulate key molecular pathways involved in the migration of PN. Using co-immunoprecipitation and proximity ligation assays, I discovered that DGCR2 is part of the REELIN complex, a key pathway regulating cortical neuron migration.(17) Moreover, Dgcr2 KD affected the REELIN-dependent phosphorylation of Akt and the expression of REELIN-dependent genes. This results allowed me to uncover the molecular and cellular mechanisms through which the SZ-risk gene Dgcr2 acts on early steps of cortical circuit formation. As a next step and in a collaborative manner, I aimed to assess the impact of Dgcr2 KD on the later functional maturation of upper-layer PN in the medial prefrontal cortex (mPFC), a key brain region involved in schizophrenia. At more mature time point (postnatal day 30), we found that Dgcr2 KD alters the morphology of the apical dendritic arbors of PN. Overall, this study revealed novel molecular mechanisms involved in schizophrenia-related developmental alterations, and opens the way to study in more details the functional impact of such early cortical circuits impairments on schizophrenia-related phenotypes
Molecular controls over cortical interneuron subtype migration
No full textThe migration of GABAergic inhibitory interneurons plays a critical role in the assembly of cortical circuits, and alterations in this process are associated to psychiatric-relevant phenotypes. In mice about 70% of cortical interneurons are generated in the medial ganglionic eminences (MGE) of the subpallium, whereas about 30% originate from the caudal ganglionic eminences (CGE) and to a smaller extent in the preoptic area (PoA). The molecular mechanisms regulating the migration of MGE-derived interneurons have been the focus of many studies in the field, whereas little is know on molecular pathways controlling CGE-derived interneuron migration. In this work, I aimed to investigate the molecular controls over the migration of cortical interneurons (cINs) preferentially derived from the CGE. Using a microarray screen performed on CGE-derived INs, I found that the ionotropic serotonin receptor 3A (5-HT3AR) is transiently up-regulated in cINs from the CGE as they invade the cortical plate. Fate-mapping experiments revealed that the 5-HT3AR is specifically expressed in CGE but not MGE-derived INs. To assess the role of the 5-HT3AR in the migration of CGE INs, we used a combination of methods, including time-lapse imaging, calcium recordings and genetic manipulations. Functional investigations including calcium imaging and migration assays indicated that CGE INs increased their responsiveness to 5-HT3AR activation specifically during CP invasion. Genetic loss-of-function experiments combined to time-lapse imaging and in vivo grafts revealed a cell-autonomous requirement for the 5-HT3AR in regulating the migration of INs into the cortical plate. Altered migration into the CP due to 5-HT3AR deletion led to the persistent laminar mispositioning of a specific subtype of reelin-expressing interneurons. Interestingly this phenotype could be observed in a mouse model of serotonin depletion, the Tph2-KO mice. Finally, to identify 5-HT3AR-dependent down-stream genes regulating migration of cINs, I performed a microarray screen on CGE-derived cINs from Htr3a-KO mice. Using this strategy, I identified the guidance receptor PlexinA4 as a candidate gene that failed to normally up-regulate in Htr3a-KO cINs specifically during the phase of CP invasion. Functional in vivo studies provided evidence that PlexinA4 regulates the positioning of cINs. Taken together, these results reveal a mechanism whereby the time-specific upregulation of the 5-HT3AR is required for the migration and positioning of cINs into the developing cortex, and suggest that PlexinA4 could be a functional downstream target of the 5-HT3AR. Given the implication of interneuron dysfunction and early-life serotonin dysregulation in vulnerability to neuropsychiatric disorders, the 5-HT3AR represents an interesting and novel cell-type specific developmental target of early-life serotonin
Role of the serotonin receptor 6 in cortical circuit formation
No full textThe formation of a laminar structure such as the mammalian neocortex relies on the coordinated migration of different subtypes of excitatory pyramidal neurons in specific layers. Cyclin-dependent kinase 5 (Cdk5) is a master regulator of pyramidal neuron migration. Recently, we have shown that Cdk5 binds to the serotonin 6 receptor (5-HT6R), a G protein-coupled receptor (GPCR). Here, we investigated the role of the 5-HT6R in the positioning and migration of pyramidal neurons during mouse corticogenesis. We report that constitutive expression of the 5-HT6R controls pyramidal neuron migration through an agonist-independent mechanism that requires cyclin-dependent kinase 5 activity. These data provide the first in vivo evidence of a role for constitutive activity at a GPCR in neocortical radial migration
Investigating the expression and function of CGE-derived interneurons
No full textGABAergic interneurons (INs) account for about 20-30% of the whole neuronal population in the neocortex and are crucial to establish inhibitory modulation in cortical microcircuits. A wide diversity of cortical interneuron subtypes are described in the neocortex and developmental studies have provided new insights on the classification of cortical interneuron subtypes. During development, cortical INs originate from distinct areas of the subpallium, more specifically from the medial (MGE) and caudal (CGE) ganglionic eminences. After their generation, from these specific subregions they first tangentially migrate into the pallium and then invade the cortical plate..
Dissecting and manipulating Htr3a-expressing cortical interneuron diversity
No full textCortical GABAergic interneurons constitute a highly diverse population in terms of embryonic origin, molecular identity, morphological and connectivity features, electrophysiological properties and laminar distribution. This large cellular diversity makes it difficult to study the specific function of inhibitory interneuronal subtypes in cortical microcircuits. Approximately 30% of cortical GABAergic interneurons are classified based on the expression of a specific serotoninergic receptor, the ionotropic serotonin receptor 5HT3a (Htr3a) and are often studied using the Htr3a-GFP mouse line. This population of Htr3a-expressing interneurons mainly arises from the embryonic caudal ganglionic eminence (CGE) and the study of its large diversity is a main focus of our laboratory..
Role of early activity in neuronal migration
No full textThe migration of cortical neuron subtypes is spatially and temporally coordinated by variety of cell intrinsic and extrinsic cues. Among cell-extrinsic cues, GABA, glutamate as well as neuromodulators such as serotonin have been shown to regulate the migration of different subtypes of neurons, including interneurons (INs) and pyramidal neurons (PNs). To further investigate the role of early activity in neuronal migration, I used an in vitro optogenetic and an in vivo chemogenetic approaches in order to manipulate early activity during development. I found that increased calcium transients in migrating cortical neurons could act as a “stop signal” that promotes differentiation. The mechanisms allowing migrating neurons to gradually increase calcium transient frequency during migration could be due to increased expression of receptors and voltage-gated ions. This would render migrating cortical neurons more responsive to cell-extrinsic network activity and trigger calcium-dependent down-stream transcriptional cascades instructing terminal differentiation
Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study
No full textLithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ)
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