4.7 Article

Postnatal Tshz3 Deletion Drives Altered Corticostriatal Function and Autism Spectrum Disorder-like Behavior

期刊

BIOLOGICAL PSYCHIATRY
卷 86, 期 4, 页码 274-285

出版社

ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2019.03.974

关键词

Autism spectrum disorder; Cortex; Sociability; Stereotypies; Striatum; Synaptopathy

资金

  1. French National Research Agency (ANR) TSHZ3inASD project [ANR-17-CE16-0030-01]
  2. Federation pour la Recherche sur le Cerveau (FRC)
  3. Centre National de la Recherche Scientifique (CNRS)
  4. Institut National de la Sante et de la Recherche Medicale (INSERM)
  5. Aix Marseille Univ
  6. Investments for the Future program (France-BioImaging) Grant [ANR-10-INSB-04-01]
  7. France Genomique national infrastructure Investissement d'Avenir Grant [ANR-10-INSB-09]
  8. A*MIDEX foundation
  9. French ANR - French Government Investissements d'Avenir program (nEURo*AMU) [ANR-17-EURE-0029]
  10. Agence Nationale de la Recherche (ANR) [ANR-17-CE16-0030] Funding Source: Agence Nationale de la Recherche (ANR)

向作者/读者索取更多资源

BACKGROUND: Heterozygous deletion of the TSHZ3 gene, encoding for the teashirt zinc-finger homeobox family member 3 (TSHZ3) transcription factor that is highly expressed in cortical projection neurons (CPNs), has been linked to an autism spectrum disorder (ASD) syndrome. Similarly, mice with Tshz3 haploinsufficiency show ASD-like behavior, paralleled by molecular changes in CPNs and corticostriatal synaptic dysfunctions. Here, we aimed at gaining more insight into when and where TSHZ3 is required for the proper development of the brain, and its deficiency crucial for developing this ASD syndrome. METHODS: We generated and characterized a novel mouse model of conditional Tshz3 deletion, obtained by crossing Tshz3(flox/flox) with CaMKIIalpha-Cre mice, in which Tshz3 is deleted in CPNs from postnatal day 2 to 3 onward. We characterized these mice by a multilevel approach combining genetics, cell biology, electrophysiology, behavioral testing, and bioinformatics. RESULTS: These conditional Tshz3 knockout mice exhibit altered cortical expression of more than 1000 genes, similar to 50% of which have their human orthologue involved in ASD, in particular genes encoding for glutamatergic synapse components. Consistently, we detected electrophysiological and synaptic changes in CPNs and impaired corticostriatal transmission and plasticity. Furthermore, these mice showed strong ASD-like behavioral deficits. CONCLUSIONS: Our study reveals a crucial postnatal role of TSHZ3 in the development and functioning of the corticostriatal circuitry and provides evidence that dysfunction in these circuits might be determinant for ASD pathogenesis. Our conditional Tshz3 knockout mouse constitutes a novel ASD model, opening the possibility for an early postnatal therapeutic window for the syndrome linked to TSHZ3 haploinsufficiency.

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