4.6 Article

Camk2a-Cre and Tshz3 Expression in Mouse Striatal Cholinergic Interneurons: Implications for Autism Spectrum Disorder

期刊

FRONTIERS IN GENETICS
卷 12, 期 -, 页码 -

出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fgene.2021.683959

关键词

Camk2a-Cre; TSHZ3; striatal cholinergic interneurons; autism spectrum disorder; Mus musculus

资金

  1. France-BioImaging/PiCsL infrastructure [ANR-10-INSB-04-01]
  2. Excellence Initiative of Aix-Marseille University A* MIDEX Investissements d'Avenir program [AMX-19-IET-004]
  3. MarMara [AMX-19-IET-007]
  4. NeuroSchool
  5. Aix-Marseille University graduate school in neuroscience by the A* MIDEX
  6. Investissements d'Avenir program (nEURo*AMU) [ANR-17EURE-0029]
  7. French Research National Agency (ANR) TSHZ3inASD project grant [nffi ANR-17-CE16-0030-01]
  8. Federation pour la Recherche sur le Cerveau (FRC)
  9. Centre National de la Recherche Scientifique (CNRS)
  10. Aix-Marseille University
  11. MESRI (Ministere de l'Enseignement Superieur, de la Recherche et de l'Innovation)
  12. [ANR-17-CE16-0030-01]

向作者/读者索取更多资源

This study revealed that Tshz3 is mainly expressed in striatal cholinergic interneurons (SCINs) and can be deleted efficiently by the Camk2a-Cre transgene. The findings help reinterpret experiments using Camk2a-Cre-dependent gene manipulations and provide insights into the cellular and molecular mechanisms underlying ASD-related behavioral abnormalities observed in Tshz3 mouse models.
Camk2a-Cre mice have been widely used to study the postnatal function of several genes in forebrain projection neurons, including cortical projection neurons (CPNs) and striatal medium-sized spiny neurons (MSNs). We linked heterozygous deletion of TSHZ3/Tshz3 gene to autism spectrum disorder (ASD) and used Camk2a-Cre mice to investigate the postnatal function of Tshz3, which is expressed by CPNs but not MSNs. Recently, single-cell transcriptomics of the adult mouse striatum revealed the expression of Camk2a in interneurons and showed Tshz3 expression in striatal cholinergic interneurons (SCINs), which are attracting increasing interest in the field of ASD. These data and the phenotypic similarity between the mice with Tshz3 haploinsufficiency and Camk2a-Cre-dependent conditional deletion of Tshz3 (Camk2a-cKO) prompted us to better characterize the expression of Tshz3 and the activity of Camk2a-Cre transgene in the striatum. Here, we show that the great majority of Tshz3-expressing cells are SCINs and that all SCINs express Tshz3. Using lineage tracing, we demonstrate that the Camk2a-Cre transgene is expressed in the SCIN lineage where it can efficiently elicit the deletion of the Tshz3-floxed allele. Moreover, transcriptomic and bioinformatic analysis in Camk2a-cKO mice showed dysregulated striatal expression of a number of genes, including genes whose human orthologues are associated with ASD and synaptic signaling. These findings identifying the expression of the Camk2a-Cre transgene in SCINs lineage lead to a reappraisal of the interpretation of experiments using Camk2a-Cre-dependent gene manipulations. They are also useful to decipher the cellular and molecular substrates of the ASD-related behavioral abnormalities observed in Tshz3 mouse models.

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