Publications by authors named "Mélanie Druart"

3 Publications

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

Mol Psychiatry 2021 Apr 9. Epub 2021 Apr 9.

INSERM UMR-S 1270, Paris, France.

Accumulating 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.
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http://dx.doi.org/10.1038/s41380-021-01081-6DOI Listing
April 2021

An Etiological Foxp2 Mutation Impairs Neuronal Gain in Layer VI Cortico-Thalamic Cells through Increased GABA/GIRK Signaling.

J Neurosci 2020 10 5;40(44):8543-8555. Epub 2020 Oct 5.

Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche-S 1270, Paris 75005, France

A rare mutation affecting the Forkhead-box protein P2 (FOXP2) transcription factor causes a severe monogenic speech and language disorder. Mice carrying an identical point mutation to that observed in affected patients (Foxp2 mice) display motor deficits and impaired synaptic plasticity in the striatum. However, the consequences of the mutation on neuronal function, in particular in the cerebral cortex, remain little studied. Foxp2 is expressed in a subset of Layer VI cortical neurons. Here, we used Ntsr1-EGFP mice to identify Foxp2+ neurons in the mouse auditory cortex We studied the functional impact of the R552H mutation on the morphologic and functional properties of Layer VI cortical neurons from Ntsr1-EGFP; Foxp2 male and female mice. The complexity of apical, but not basal dendrites was significantly lower in Foxp2 cortico-thalamic neurons than in control Foxp2 neurons. Excitatory synaptic inputs, but not inhibitory synaptic inputs, were decreased in Foxp2 mice. In response, homeostatic mechanisms would be expected to increase neuronal gain, i.e., the conversion of a synaptic input into a firing output. However, the intrinsic excitability of Foxp2+ cortical neurons was lower in Foxp2 neurons. A-type and delayed-rectifier (DR) potassium currents, two putative transcriptional targets of Foxp2, were not affected by the mutation. In contrast, GABA/GIRK signaling, another presumed target of Foxp2, was increased in mutant neurons. Blocking GIRK channels strongly attenuated the difference in intrinsic excitability between wild-type (WT) and Foxp2 neurons. Our results reveal a novel role for Foxp2 in the control of neuronal input/output homeostasis. Mutations of the Forkhead-box protein 2 (FOXP2) gene in humans are the first known monogenic cause of a speech and language disorder. The Foxp2 mutation may directly affect neuronal development and function in neocortex, where Foxp2 is expressed. Brain imaging studies in patients with a heterozygous mutation in FOXP2 showed abnormalities in cortical language-related regions relative to the unaffected members of the same family. However, the role of Foxp2 in neocortical neurons is poorly understood. Using mice with a Foxp2 mutation equivalent to that found in patients, we studied functional modifications in auditory cortex neurons We found that mutant neurons exhibit alterations of synaptic input and GABAB/GIRK signaling, reflecting a loss of neuronal homeostasis.
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http://dx.doi.org/10.1523/JNEUROSCI.2615-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605419PMC
October 2020

Emerging Roles of Complement in Psychiatric Disorders.

Front Psychiatry 2019 21;10:573. Epub 2019 Aug 21.

INSERM UMR-S 1270, Paris, France.

The complement system consists of more than 30 proteins that have long been known to participate to the immune defence against pathogens and to the removal of damaged cells. Their role, however, extends beyond immunity and clearance of altered "self" components in the periphery. In particular, complement proteins can be induced by all cell types in the brain. Recent discoveries highlight the role of complement in normal and pathological brain development. Specifically, the complement system mediates synaptic pruning, a developmental process whereby supernumerary synapses are eliminated in the immature brain. The complement system has been implicated in pathological synapse elimination in schizophrenia, West Nile virus infection, and lupus, all of which are associated with psychiatric manifestations. Complement also contributes to synapse loss in neurodegenerative conditions. This review provides a brief overview of the well-studied role of complement molecules in immunity. The contribution of complement to embryonic and adult neurogenesis, neuronal migration, and developmental synaptic elimination in the normal brain is reviewed. We discuss the role of complement in synapse loss in psychiatric and neurological diseases and evaluate the therapeutic potential of complement-targeting drugs for brain disorders.
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http://dx.doi.org/10.3389/fpsyt.2019.00573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712161PMC
August 2019