Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome.
Perturbation of the excitation/inhibition (E/I) balance leads to neurodevelopmental diseases including to autism spectrum disorders, intellectual disability, and epilepsy. Loss-of-function mutations in the DYRK1A gene, located on human chromosome 21 (Hsa21,) lead to an intellectual disability syndro...
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2021
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oai:doaj.org-article:d01eb288fea740cd83a75fa843e3f2c82021-12-02T20:03:01ZDyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome.1553-73901553-740410.1371/journal.pgen.1009777https://doaj.org/article/d01eb288fea740cd83a75fa843e3f2c82021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009777https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Perturbation of the excitation/inhibition (E/I) balance leads to neurodevelopmental diseases including to autism spectrum disorders, intellectual disability, and epilepsy. Loss-of-function mutations in the DYRK1A gene, located on human chromosome 21 (Hsa21,) lead to an intellectual disability syndrome associated with microcephaly, epilepsy, and autistic troubles. Overexpression of DYRK1A, on the other hand, has been linked with learning and memory defects observed in people with Down syndrome (DS). Dyrk1a is expressed in both glutamatergic and GABAergic neurons, but its impact on each neuronal population has not yet been elucidated. Here we investigated the impact of Dyrk1a gene copy number variation in glutamatergic neurons using a conditional knockout allele of Dyrk1a crossed with the Tg(Camk2-Cre)4Gsc transgenic mouse. We explored this genetic modification in homozygotes, heterozygotes and combined with the Dp(16Lipi-Zbtb21)1Yey trisomic mouse model to unravel the consequence of Dyrk1a dosage from 0 to 3, to understand its role in normal physiology, and in MRD7 and DS. Overall, Dyrk1a dosage in postnatal glutamatergic neurons did not impact locomotor activity, working memory or epileptic susceptibility, but revealed that Dyrk1a is involved in long-term explicit memory. Molecular analyses pointed at a deregulation of transcriptional activity through immediate early genes and a role of DYRK1A at the glutamatergic post-synapse by deregulating and interacting with key post-synaptic proteins implicated in mechanism leading to long-term enhanced synaptic plasticity. Altogether, our work gives important information to understand the action of DYRK1A inhibitors and have a better therapeutic approach.Véronique BraultThu Lan NguyenJavier Flores-GutiérrezGiovanni IaconoMarie-Christine BirlingValérie LalanneHamid MezianeAntigoni ManousopoulouGuillaume PavlovicLoïc LindnerMohammed SelloumTania SorgEugene YuSpiros D GarbisYann HéraultPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 9, p e1009777 (2021) |
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Genetics QH426-470 |
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Genetics QH426-470 Véronique Brault Thu Lan Nguyen Javier Flores-Gutiérrez Giovanni Iacono Marie-Christine Birling Valérie Lalanne Hamid Meziane Antigoni Manousopoulou Guillaume Pavlovic Loïc Lindner Mohammed Selloum Tania Sorg Eugene Yu Spiros D Garbis Yann Hérault Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome. |
| description |
Perturbation of the excitation/inhibition (E/I) balance leads to neurodevelopmental diseases including to autism spectrum disorders, intellectual disability, and epilepsy. Loss-of-function mutations in the DYRK1A gene, located on human chromosome 21 (Hsa21,) lead to an intellectual disability syndrome associated with microcephaly, epilepsy, and autistic troubles. Overexpression of DYRK1A, on the other hand, has been linked with learning and memory defects observed in people with Down syndrome (DS). Dyrk1a is expressed in both glutamatergic and GABAergic neurons, but its impact on each neuronal population has not yet been elucidated. Here we investigated the impact of Dyrk1a gene copy number variation in glutamatergic neurons using a conditional knockout allele of Dyrk1a crossed with the Tg(Camk2-Cre)4Gsc transgenic mouse. We explored this genetic modification in homozygotes, heterozygotes and combined with the Dp(16Lipi-Zbtb21)1Yey trisomic mouse model to unravel the consequence of Dyrk1a dosage from 0 to 3, to understand its role in normal physiology, and in MRD7 and DS. Overall, Dyrk1a dosage in postnatal glutamatergic neurons did not impact locomotor activity, working memory or epileptic susceptibility, but revealed that Dyrk1a is involved in long-term explicit memory. Molecular analyses pointed at a deregulation of transcriptional activity through immediate early genes and a role of DYRK1A at the glutamatergic post-synapse by deregulating and interacting with key post-synaptic proteins implicated in mechanism leading to long-term enhanced synaptic plasticity. Altogether, our work gives important information to understand the action of DYRK1A inhibitors and have a better therapeutic approach. |
| format |
article |
| author |
Véronique Brault Thu Lan Nguyen Javier Flores-Gutiérrez Giovanni Iacono Marie-Christine Birling Valérie Lalanne Hamid Meziane Antigoni Manousopoulou Guillaume Pavlovic Loïc Lindner Mohammed Selloum Tania Sorg Eugene Yu Spiros D Garbis Yann Hérault |
| author_facet |
Véronique Brault Thu Lan Nguyen Javier Flores-Gutiérrez Giovanni Iacono Marie-Christine Birling Valérie Lalanne Hamid Meziane Antigoni Manousopoulou Guillaume Pavlovic Loïc Lindner Mohammed Selloum Tania Sorg Eugene Yu Spiros D Garbis Yann Hérault |
| author_sort |
Véronique Brault |
| title |
Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome. |
| title_short |
Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome. |
| title_full |
Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome. |
| title_fullStr |
Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome. |
| title_full_unstemmed |
Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome. |
| title_sort |
dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of mrd7 and down syndrome. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/d01eb288fea740cd83a75fa843e3f2c8 |
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