Epilepsy in Dcx Knockout Mice Associated with Discrete Lamination Defects and Enhanced Excitability in the Hippocampus

Patients with Doublecortin (DCX) mutations have severe cortical malformations associated with mental retardation and epilepsy. Dcx knockout (KO) mice show no major isocortical abnormalities, but have discrete hippocampal defects. We questioned the functional consequences of these defects and report here that Dcx KO mice are hyperactive and exhibit spontaneous convulsive seizures. Changes in neuropeptide Y and calbindin expression, consistent with seizure occurrence, were detected in a large proportion of KO animals, and convulsants, including kainate and pentylenetetrazole, also induced seizures more readily in KO mice. We show that the dysplastic CA3 region in KO hippocampal slices generates sharp wave-like activities and possesses a lower threshold for epileptiform events. Video-EEG monitoring also demonstrated that spontaneous seizures were initiated in the hippocampus. Similarly, seizures in human patients mutated for DCX can show a primary involvement of the temporal lobe. In conclusion, seizures in Dcx KO mice are likely to be due to abnormal synaptic transmission involving heterotopic cells in the hippocampus and these mice may therefore provide a useful model to further study how lamination defects underlie the genesis of epileptiform activities

Études comportementales des souris invalidées pour le transporteur de la dopamine utilisées comme modèle d'analyse génétique de traits complexes

J'ai réalisé une analyse comportementale chez des souris invalidées pour le transporteur de la dopamine, responsable de sa recapture par les terminaisons pré-synaptiques. Cette étude illustre l'impact des interactions entre une mutation et l'environnement génétique dans lequel elle s'exprime à la fois au niveau physiologique (survie, développement pondéral, allaitement) et comportemental (activité spontanée, comportement maternel, réponse aux drogues). Elle souligne le rôle clé de la transmission dopaminergique dans la mise en place de la latéralisation comportementale et confirme l'implication de ce système dans la flexibilité comportementale et dans les processus d'apprentissage et de mémoire associatif. La latéralisation et les troubles cognitifs sont des marqueurs de susceptibilité à différents troubles psychiatriques. La compréhension de la contribution des processus dopaminergiques dans chacun de ces endophénotypes permettra de répondre à des questions posées par la clinique.During my thesis, I have carried out a behavioural analysis using the dopamine transporter (DAT) knockout mice. The DAT is responsible for the rapid uptake of dopamine into presynaptic terminals. We showed that changing the genetic background revealed the extent of phenotypic variation associated with the DAT mutation both at the physiological (survival, growth rate, lactation) and behavioural levels (spontaneous activity, maternal behaviour, sensitivity to psychostimulants). The data emphasised the key role of the dopaminergic transmission in the development of the behavioural lateralization, in behavioural flexibility, and as well as in associative learning and memory. The understanding of the contribution of the dopaminergic system to each of theses endophenotypes will allow us to make progress in psychiatric research.PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

Optimal breeding strategy for mouse mutant strains

International audienceDespite the published recommendations after the Banbury Conference in 1997 to maintain a mutation on controlled genetic backgrounds, maintenance of mutant strains and production of experimental groups are still too often hampered by constraints of time, space, and cost. We propose here a simple and rigorous method that allows not only the efficient production of animals, but especially the precise control of the genetic background and the generation of appropriate control groups, guaranteeing stable and reproducible observations. This method is flexible and allows optimization and adaptation of the production according to the experimental needs, thus reducing the final cost. In addition, the work of the Animal Care technicians is simplified and animal welfare is improved

Neuronal migration and its disorders affecting the CA3 region

International audienceIn this review, we focus on CA3 neuronal migration disorders in the rodent. We begin by introducing the main steps of hippocampal development, and we summarize characteristic hippocampal malformations in human. We then describe various mouse mutants showing structural hippocampal defects. Notably, genes identified in human cortical neuronal migration disorders consistently give rise to a CA3 phenotype when mutated in the mouse. We successively describe their molecular, physiological and behavioral phenotypes that together contribute to a better understanding of CA3-dependent functions. We finally discuss potential factors underlying the CA3 vulnerability revealed by these mouse mutants and that may also contribute to other human neurological and psychiatric disorders

Inflammation and Autophagy: A Convergent Point between Autism Spectrum Disorder (ASD)-Related Genetic and Environmental Factors: Focus on Aluminum Adjuvants

International audienceAutism spectrum disorder (ASD), schizophrenia, and bipolar disorder are genetically complex and heterogeneous neurodevelopmental disorders (NDDs) resulting from genetic factors and gene-environment (GxE) interactions for which onset occurs in early brain development. Recent progress highlights the link between ASD and (i) immunogenetics, neurodevelopment, and inflammation, and (ii) impairments of autophagy, a crucial neurodevelopmental process involved in synaptic pruning. Among various environmental factors causing risk for ASD, aluminum (Al)-containing vaccines injected during critical periods have received special attention and triggered relevant scientific questions. The aim of this review is to discuss the current knowledge on the role of early inflammation, immune and autophagy dysfunction in ASD as well as preclinical studies which question Al adjuvant impacts on brain and immune maturation. We highlight the most recent breakthroughs and the lack of epidemiological, pharmacokinetic and pharmacodynamic data constituting a “scientific gap”. We propose additional research, such as genetic studies that could contribute to identify populations at genetic risk, improving diagnosis, and potentially the development of new therapeutic tools

N-3 Polyunsaturated fatty acid supplementation improves hyperdopaminergic phenotypes in mice invalidated for dopamine transporter (DAT-KO)

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Cerebral Asymmetry and Behavioral Lateralization in Rats Chronically Lacking n-3 Polyunsaturated Fatty Acids

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Doublecortin Knockout Mice Show Normal Hippocampal-Dependent Memory Despite CA3 Lamination Defects

International audienceMutations in the human X-linked doublecortin gene (DCX) cause major neocortical disorganization associated with severe intellectual disability and intractable epilepsy. Although Dcx knockout (KO) mice exhibit normal isocortical development and architecture, they show lamination defects of the hippocampal pyramidal cell layer largely restricted to the CA3 region. Dcx-KO mice also exhibit interneuron abnormalities. As well as the interest of testing their general neurocognitive profile, Dcx-KO mice also provide a relatively unique model to assess the effects of a disorganized CA3 region on learning and memory. Based on its prominent anatomical and physiological features, the CA3 region is believed to contribute to rapid encoding of novel information, formation and storage of arbitrary associations, novelty detection, and short-term memory. We report here that Dcx-KO adult males exhibit remarkably preserved hippocampal-and CA3-dependant cognitive processes using a large battery of classical hippocampus related tests such as the Barnes maze, contextual fear conditioning, paired associate learning and object recognition. In addition, we show that hippocampal adult neurogenesis, in terms of proliferation, survival and differentiation of granule cells, is also remarkably preserved in Dcx-KO mice. In contrast, following social deprivation, Dcx-KO mice exhibit impaired social interaction and reduced aggressive behaviors. In addition, Dcx-KO mice show reduced behavioral lateralization. The Dcx-KO model thus reinforces the association of neuropsychiatric behavioral impairments with mouse models of intellectual disability

Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes

International audienceAccumulating evidence supports immune involvement in the pathogenesis of schizophrenia, a severe psychiatric disorder. In particular, high expression variants of C4, a gene of the innate immune complement system, were shown to confer susceptibility to schizophrenia. However, how elevated C4 expression may impact brain circuits remains largely unknown. We used in utero electroporation to overexpress C4 in the mouse prefrontal cortex. We found reduced glutamatergic input to pyramidal cells of juvenile and adult, but not of newborn C4-overexpressing (C4-OE) mice, together with decreased spine density, which mirrors spine loss observed in the schizophrenic cortex. Using time-lapse two-photon imaging in vivo, we observed that these deficits were associated with decreased dendritic spine gain and elimination in juvenile C4-OE mice, which may reflect poor formation and/or stabilization of immature spines. In juvenile and adult C4-OE mice, we found evidence for NMDA receptor hypofunction, another schizophrenia-associated phenotype, and synaptic accumulation of calcium-permeable AMPA receptors. Alterations in cortical GABAergic networks have been repeatedly associated with schizophrenia. We found that functional GABAergic transmission was reduced in C4-OE mice, in line with diminished GABA release probability from parvalbumin interneurons, lower GAD67 expression, and decreased intrinsic excitability in parvalbumin interneurons. These cellular abnormalities were associated with working memory impairment. Our results substantiate the causal relationship between an immunogenetic risk factor and several distinct cortical endophenotypes of schizophrenia and shed light on the underlying cellular mechanisms

L-DOPA Impairs Proteasome Activity in Parkinsonism through D1 Dopamine Receptor

International audienceAberrant membrane localization of dopamine D(1) receptor (D1R) is associated with L-DOPA-induced dyskinesia (LID), a major complication of L-DOPA treatment in Parkinson's disease (PD). Since the proteasome plays a central role in modulating neuronal response through regulation of neurotransmitter receptor intraneuronal fate, we hypothesized that the ubiquitine-proteasome proteolytic pathway could be impaired in LID. Those LIDs are actually associated with a striatum-specific decrease in proteasome catalytic activity and accumulation of polyubiquitinated proteins in experimental rodent and monkey parkinsonism. We then demonstrated that such decreased proteasome catalytic activity (1) results from D1R activation and (2) feed-back the D1R abnormal trafficking, i.e., its exaggerated cell surface abundance. We further showed that the genetic invalidation of the E3 ubiquitin-protein ligase parkin PD gene leads to exaggerated abnormal involuntary movements compared with wild-type mice. We thus established in an unprecedented series of experimental models that impairment of the ubiquitine-proteasome system at specific nodes (E3 ligase parkin, polyubiquitination, proteasome catalytic activity) leads to the same phenomenon, i.e., aberrant behavioral response to dopamine replacement therapy in PD, highlighting the intimate interplay between dopamine receptor and proteasome activity in a nondegenerative context