Liste des publications

Les publications de l'équipe

IF du Neurocentre

58 publications

* equal contribution
Les IF indiqués ont été collectés par le Web of Sciences en Juin 2019

02/2020 | Neurosci Biobehav Rev   IF 8
What we can learn from a genetic rodent model about autism.
Mohrle D, Fernandez M, Penagarikano O, Frick A, Allman B, Schmid S

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders that are caused by genetic and/or environmental impacts, often probably by the interaction of both. They are characterised by deficits in social communication and interaction and by restricted and repetitive behaviours and interests from early childhood on, causing significant impairment. While it is clear that no animal model captures the full complexity of ASD in humans, genetic models are extremely useful for studying specific symptoms associated with ASD and the underlying cellular and molecular mechanisms. In this review we summarize the behavioral paradigms used in rodents to model ASD symptoms as they are listed in the DSM-5. We then review existing genetic rodent models with disruptions in ASD candidate genes, and we map their phenotypes onto these behavioural paradigms. The goal of this review is to give a comprehensive overview on how ASD symptoms can be studied in animal models and to give guidance for which animal models are appropriate to study specific symptom clusters.

22/05/2019 | J Neurosci   IF 6.1
Hippocampal Mossy Fibers Synapses in CA3 Pyramidal Cells Are Altered at an Early Stage in a Mouse Model of Alzheimer's Disease.
Viana da Silva S, Zhang P, Haberl MG, Labrousse V, Grosjean N, Blanchet C, Frick A, Mulle C

Early Alzheimer's disease (AD) affects the brain non-uniformly, causing hippocampal memory deficits long before wide-spread brain degeneration becomes evident. Here we addressed whether mossy fiber inputs from the dentate gyrus onto CA3 principal cells are affected in an AD mouse model before amyloid beta plaque deposition. We recorded from CA3 pyramidal cells in a slice preparation from 6-month-old male APP/PS1 mice, and studied synaptic properties and intrinsic excitability. In parallel we performed a morphometric analysis of mossy fiber synapses following viral based labeling and 3D-reconstruction. We found that the basal structural and functional properties as well as presynaptic short-term plasticity at mossy fiber synapses are unaltered at 6 months in APP/PS1 mice. However, transient potentiation of synaptic transmission mediated by activity-dependent release of lipids was abolished. Whereas the presynaptic form of mossy fiber long-term potentiation (LTP) was not affected, the postsynaptic LTP of NMDAR-EPSCs was reduced. In addition, we also report an impairment in feedforward inhibition in CA3 pyramidal cells. This study, together with our previous work describing deficits at CA3-CA3 synapses, provides evidence that early AD affects synapses in a projection-dependent manner at the level of a single neuronal population.SIGNIFICANCE STATEMENT Because loss of episodic memory is considered the cognitive hallmark of Alzheimer's disease (AD), it is important to study whether synaptic circuits involved in the encoding of episodic memory are compromised in AD mouse models. Here we probe alterations in the synaptic connections between the dentate gyrus and CA3, which are thought to be critical for enabling episodic memories to be formed and stored in CA3. We found that forms of synaptic plasticity specific to these synaptic connections are markedly impaired at an early stage in a mouse model of AD, before deposition of beta amyloid plaques. Together with previous work describing deficits at CA3-CA3 synapses, we provide evidence that early AD affects synapses in an input-dependent manner within a single neuronal population.

09/2018 | Eur J Neurosci   IF 2.8
Peripheral delta opioid receptors mediate duloxetine antiallodynic effect in a mouse model of neuropathic pain.
Ceredig RA, Pierre F, Doridot S, Alduntzin U, Salvat E, Yalcin I, Gaveriaux-Ruff C, Barrot M, Massotte D

Peripheral delta opioid (DOP) receptors are essential for the antiallodynic effect of the tricyclic antidepressant nortriptyline. However, the population of DOP-expressing cells affected in neuropathic conditions or underlying the antiallodynic activity of antidepressants remains unknown. Using a mouse line in which DOP receptors were selectively ablated in cells expressing Nav1.8 sodium channels (DOP cKO), we established that these DOP peripheral receptors were mandatory for duloxetine to alleviate mechanical allodynia in a neuropathic pain model based on sciatic nerve cuffing. We then examined the impact of nerve cuffing and duloxetine treatment on DOP-positive populations using a knock-in mouse line expressing a fluorescent version of the DOP receptor fused with the enhanced green fluorescent protein (DOPeGFP). Eight weeks postsurgery, we observed a reduced proportion of DOPeGFP-positive small peptidergic sensory neurons (calcitonin gene-related peptide (CGRP) positive) in dorsal root ganglia and a lower density of DOPeGFP-positive free nerve endings in the skin. These changes were not present in nerve-injured mice chronically treated with oral duloxetine. In addition, increased DOPeGFP translocation to the plasma membrane was observed in neuropathic conditions but not in duloxetine-treated neuropathic mice, which may represent an additional level of control of the neuronal activity by DOP receptors. Our results therefore established a parallel between changes in the expression profile of peripheral DOP receptors and mechanical allodynia induced by sciatic nerve cuffing.

17/08/2018 | neuroimmunomodulation   IF 1.4
Reduced CD4 T Lymphocytes in Lymph Nodes of the Mouse Model of Autism Induced by Valproic Acid.
Baronio D, Bauer-Negrini G, Castro K, Della-Flora Nunes G, Riesgo R, Mendes-da-Cruz DA, Savino W, Gottfried C, Bambini-Junior V

OBJECTIVE: Considering the potential role of lymphocytes in the pathophysiology of autism spectrum disorder (ASD), we aimed to evaluate possible alterations of T cell pools in the lymphoid organs of an animal model of autism induced by valproic acid (VPA). Pregnant Swiss mice received a single intraperitoneal injection of 600 mg/kg of VPA (VPA group) or saline (control group) on day 11 of gestation. Male offspring were euthanized on postnatal day 60 for removal of thy-muses, spleens, and a pool of inguinal, axillary and brachial lymph nodes. Cellularity was evaluated, and flow cytometry analysis was performed on cell suspensions incubated with the mouse antibodies anti-CD3-FITC, anti-CD4-PE, and anti-CD8-PE-Cy7. We observed that the prenatal exposure to VPA induced a reduction in the numbers of CD3+CD4+ T cells in their lymph nodes when compared to the control animals. This was specific since it was not seen in the thymus or spleen. The consistent decrease in the number of CD4+ T cells in subcutaneous lymph nodes of mice from the animal model of autism may be related to the allergic symptoms frequently observed in ASD. Further research is necessary to characterize the immunological patterns in ASD and the connection with the pathophysiology of this disorder.

11/06/2018 | Sci Rep   IF 4
D5 dopamine receptors control glutamatergic AMPA transmission between the motor cortex and subthalamic nucleus.
Froux L, Le Bon-Jego M, Miguelez C, Normand E, Morin S, Fioramonti S, Barresi M, Frick A, Baufreton J, Taupignon A

Corticofugal fibers target the subthalamic nucleus (STN), a component nucleus of the basal ganglia, in addition to the striatum, their main input. The cortico-subthalamic, or hyperdirect, pathway, is thought to supplement the cortico-striatal pathways in order to interrupt/change planned actions. To explore the previously unknown properties of the neurons that project to the STN, retrograde and anterograde tools were used to specifically identify them in the motor cortex and selectively stimulate their synapses in the STN. The cortico-subthalamic neurons exhibited very little sag and fired an initial doublet followed by non-adapting action potentials. In the STN, AMPA/kainate synaptic currents had a voltage-dependent conductance, indicative of GluA2-lacking receptors and were partly inhibited by Naspm. AMPA transmission displayed short-term depression, with the exception of a limited bandpass in the 5 to 15 Hz range. AMPA synaptic currents were negatively controlled by dopamine D5 receptors. The reduction in synaptic strength was due to postsynaptic D5 receptors, mediated by a PKA-dependent pathway, but did not involve a modified rectification index. Our data indicated that dopamine, through post-synaptic D5 receptors, limited the cortical drive onto STN neurons in the normal brain.

18/04/2018 | Cereb Cortex   IF 5.4
Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories
Zerbi Valerio, Giovanna D. Ielacqua, Marija Markicevic, Matthias Georg Haberl, Mark H. Ellisman, A-Bhaskaran A, Frick A, Markus Rudin, Nicole Wenderoth

Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-speciï¬c for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1â/y) and contactin-associated (CNTNAP2â/â) knockout mice. Young Fmr1â/y mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2â/â mice, while major connectivity deï¬cits in prefrontal and limbic pathways developed between adolescence and adulthood. These ï¬ndings are supported by viral tracing and electron micrograph approaches and deï¬ne 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly inï¬uences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes.

26/12/2017 | arch environ occup health   IF 1.5
Mental health in underground coal miners.
Joaquim AC, Lopes M, Stangherlin L, Castro K, Ceretta LB, Longen WC, Ferraz F, Perry IDS

As mental health goes beyond the simple absence of mental disorders, this paper characterized mental health components in 89 underground coal miners in southern Brazil. This is a cross-sectional study, that detected a low prevalence of depression; light or moderate anxiety in 13% of the workers; self-perception of good health; life quality and good psychological capacity in most of the participants; poor sleep quality in half of them; reverse correlations between anxiety and life quality, and anxiety and psychological capital; positive correlations between psychological capital and life quality; associations between self-perception of health, time, and sleep quality; associations between anxiety and sleep duration and quality; and between alcohol consumption and location at work (front, rear, or variable). The results suggest vulnerabilities regarding anxiety and sleep quality. However, there is a potential coping of determinants that impact on mental health.

12/2017 | minerva pediatr   IF 0.8
Bioelectrical impedance analysis: body composition in children and adolescents with Down syndrome.
Goncalves Machado A, Lummertz Magenis M, Bongiolo AM, Castro K, da Silva MA, Schweigert Perry ID

24/10/2017 | Nat Commun   IF 11.9
Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice.
Aloisi E, Le Corf K, Dupuis J, Zhang P, Ginger M, Labrousse V, Spatuzza M, Georg Haberl M, Costa L, Shigemoto R, Tappe-Theodor A, Drago F, Vincenzo Piazza P, Mulle C, Groc L, Ciranna L, Catania MV, Frick A

Metabotropic glutamate receptor subtype 5 (mGluR5) is crucially implicated in the pathophysiology of Fragile X Syndrome (FXS); however, its dysfunction at the sub-cellular level, and related synaptic and cognitive phenotypes are unexplored. Here, we probed the consequences of mGluR5/Homer scaffold disruption for mGluR5 cell-surface mobility, synaptic N-methyl-D-aspartate receptor (NMDAR) function, and behavioral phenotypes in the second-generation Fmr1 knockout (KO) mouse. Using single-molecule tracking, we found that mGluR5 was significantly more mobile at synapses in hippocampal Fmr1 KO neurons, causing an increased synaptic surface co-clustering of mGluR5 and NMDAR. This correlated with a reduced amplitude of synaptic NMDAR currents, a lack of their mGluR5-activated long-term depression, and NMDAR/hippocampus dependent cognitive deficits. These synaptic and behavioral phenomena were reversed by knocking down Homer1a in Fmr1 KO mice. Our study provides a mechanistic link between changes of mGluR5 dynamics and pathological phenotypes of FXS, unveiling novel targets for mGluR5-based therapeutics.

10/2017 | Clin Chim Acta   IF 2.7
Leptin concentrations and SCD-1 indices in classical homocystinuria: Evidence for the role of sulfur amino acids in the regulation of lipid metabolism.
Poloni S, Spritzer PM, Mendes RH, D'Almeida V, Castro K, Sperb-Ludwig F, Kugele J, Tucci S, Blom HJ, Schwartz IVD

BACKGROUND: We describe body composition, lipid metabolism and Stearoyl-CoA desaturase-1 (SCD-1) indices in patients with classical homocystinuria (HCU). METHODS: Eleven treated HCU patients and 16 healthy controls were included. Body composition and bone mineral density were assessed by dual X-ray absorptiometry. Sulfur amino acids (SAA) and their derivatives (total homocysteine, cysteine, methionine, S-adenosylmethionine, S-adenosylhomocysteine, and glutathione), lipids (free fatty acids, acylcarnitines, triglycerides and lipoproteins), glucose, insulin, leptin, adiponectin, and isoprostanes were measured in plasma. Insulin resistance was evaluated by HOMA-IR. To estimate liver SCD-1 activity, SCD-16 [16:1(n-7)/16:0] and SCD-18 [18:1(n-9)/18:0] desaturation indices were determined. RESULTS: In HCU patients, SCD-16 index was significantly reduced (p=0.03). A trend of an association of SCD-16 index with cysteine was observed (r=0.624, p=0.054). HCU patients displayed lower lean mass (p<0.05), with no differences in fat mass percentage. Leptin and low-density lipoprotein concentrations were lower in HCU patients (p<0.05). Femur bone mineral density Z-scores were correlated with plasma cysteine (r=0.829; p=0.04) and total homocysteine (r=-0.829; p=0.04) in HCU patients. CONCLUSIONS: We report alterations in leptin and SCD-1 in HCU patients. These results agree with previous findings from epidemiologic and animal studies, and support a role for SAA on lipid homeostasis.