Dorian Chabbert1, Xavier Caubit1, Pierre L Roubertoux2, Michèle Carlier3, Bianca Habermann4, Bernard Jacq1, Pascal Salin1, Mehdi Metwaly1, Christina Frahm5, Ahmed Fatmi1, Alistair N Garratt6, Dany Severac7, Emeric Dubois7, Lydia Kerkerian-Le Goff1, Laurent Fasano8, Paolo Gubellini9. 1. Aix Marseille Univ, CNRS, IBDM, Marseille, France. 2. Aix Marseille Univ, INSERM, MMG, Marseille, France. 3. Aix Marseille Univ, CNRS, LPC, Marseille, France. 4. Aix Marseille Univ, CNRS, IBDM, Marseille, France; Aix Marseille Univ, INSERM, TAGC, Marseille, France. 5. Max Delbrück Center for Molecular Medicine, Berlin, Germany. 6. Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité University Hospital Berlin, Berlin, Germany. 7. Univ Montpellier, CNRS, INSERM, MGX, Montpellier, France. 8. Aix Marseille Univ, CNRS, IBDM, Marseille, France. Electronic address: laurent.fasano@univ-amu.fr. 9. Aix Marseille Univ, CNRS, IBDM, Marseille, France. Electronic address: paolo.gubellini@univ-amu.fr.
Abstract
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 Tshz3flox/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, ∼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.
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 Tshz3flox/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, ∼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.