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Control Of The Gabaergic System By Dyrk1a In Mouse Models Of Trisomy 21

Reference : PhD Véronique BRAULT

Offer publication : April 5, 2016

Cognitive deficits observed in Trisomy 21 (T21)(or Down syndrome, DS) have been linked failure in the control of the excitatory/inhibitory balance that lead to overproduction of the GABA neurotransmitter and to inhibition of of glutamatergic receptors. Excitatory/inhibitory balance is essential for memorization. Dysfunction of the balance leads to neurodeveloppemental diseases associated to autism spectrum disorders and intellectual disability such as the DS, but also to neurological diseases such as schizophrenia and epilepsy. The DYRK1A gene present on human chromosome 21 (Hsa21) codes for a kinase with numerous substrates. Haploinsuficiency of this gene leads to an intellectual disability syndrome
associated with microcephaly, epilepsy and autistic roubles (MRD7). In mice, haploinsufficiency of Dyrk1a leads to decreased neonatal viability and decreased brain size with altered microarchitecture of pyramidal cells in the cerebral cortex. DYRK1A is also the major candidate for neurological
phenotypes observed in DS. Mouse models overexpressing Dyrk1a show deficits in learning and memory and deficits in endocytosis and synaptic function. Recent studies indicate that overexpression of Dyrk1a in mouse models of T21 is responsible for deficit in the synaptic transmission and for the GABA overexpression observed in those models. Interestingly, Dyrk1a overexpression in TgDyrk1a mice protect those mice from PTZ-induced seizure.

The thesis project aims at defining the physiologic and pathophysiologic role of DYRK1A in the control of the excitatory/inhibitory balance by studying its impact in the GABAergic system. This project will benefit from several mouse models that we have in the laboratory: a Dyrk1a<KO> line, a
conditional allele for Dyrk1a inactivation (Dyrk1a<cKO>) and the Ts1Yey model for DS that has a 22.9 Mb duplication on mouse chromosome 16 with 140 Hsa21 orthologs (one of which being Dyrk1a). Impact of Dyrk1a dosage in GABAergic neurons will be studied using a genetic approach: we will use the conditional Dyrk1a <cKO> line, crossed with the Tg(dlx6a-cre)1Mekk line (TgDlx-Cre) that expresses the Cre recombinase in GABAergic
interneurons. Those mouse lines will enable to delete one copy of Dyrk1a in GABAergic neurons and, combined with the Ts1Yey trisomic model, will enable to return to two copies of Dyrk1a in this model only in GABAergic neurons and see if normalisation of Dyrk1a gene dosage in interneurons is sufficient to rescue the neurologic phenotypes observed in Ts1Yey mice. The Ts1Yey model has a deficit in working memory (Y maze), recognition
memory (Novel Object recognition test), fear-associated memory (Fear conditioning test) and hippocampal synaptic plasticity as seen by reduced long-term potentiation (LTP). In order to see if the impact of Dyrk1a on those functions occurs via the GABAergic system, we will generate Ts1Yey; Dyrk1aDlx/+ mice and analyse those mice for restoration of cognitive functions and LTP. We will also analyse the impact of Dyrk1a haploinsufficiency
on those functions in Dyrk1aDlx/+ mice. As Dyrk1a overexpression protects mice from PTZ-induced seizure while its happloinsufficiency leads toincreased sensitivity, we will also challenge Ts1Yey, Ts1Yey; Dyrk1aDlx/+ and Dyrk1aDlx/+ mice with this seizure-provoking agent to explore how Dyrk1a modulates GABA-mediated inhibition to control the excitatory/inhibitory balance. We will then analyse those mice at the cellular and molecular levels: number and morphology of the neurons, proteomic analysis in order to determine the signalling pathways that are impacted by the change of Dyrk1a dosage and compare them with Ts1Yey, TgDyrk1a and Dyrk1a<KO/+> mice to decipher the impact of Dyrk1a gene dosage in GABAergic neuron vs its global impact (Dyrk1a is expressed in different populations of neurons).

- WISHED SKILLS : The candidate must hold a Master degree in biology and have previously worked in a research laboratory. Knowledge in neurology, molecular biology and eventually genetics are required. He or she should be motivated, rigorous able to work in a team and to acquire independence. Finally, he or she should have good oral expression and writing capacities in English.

- EXPERTISES WHICH WILL BE ACQUIRED DURING THE TRAINING : The candidate will learn basic techniques in mouse genetics and phenotyping (maintenance of colonies, genotyping, Behavioral and physiological analyses), in molecular biology (DNA, RNA and protein extraction and analysis) and cell biology (primary neuronal cells cultures, immunofluorescence, classical and confoncal microscopy). He or she will also benefit from a training in new techniques of genomic and transcriptional analyses (transcriptome, proteome and RNAseq) and will have the occasion to collaborate with French and European partners.

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Application Deadline : Dec. 31, 2016

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