Role of TSHZ3 in the development and function of neuronal systems involved in autism spectrum disorder – TSHZ3inASD

Autism spectrum disorder (ASD) defines a heterogeneous group of neurodevelopmental disorders that share core behavioral abnormalities, characterized by impairments in social communication and interaction, restricted interests and repetitive behaviors. ASD has a large genetic component and integrative genomic analyses have converged on altered development of glutamatergic projection neurons of the cerebral cortex as a possible substrate. Recently, we identified the gene TSHZ3 as the minimal region of overlap for 19q12 heterozygous deletions in patients with a new syndrome including autistic features and provided evidence, from studies in mouse models, for a link between heterozygous Tshz3 deletion, defects in cortical projection neurons (CPNs) and ASD-like deficits (Caubit et al., 2016).
The identification of TSHZ3 as a candidate gene involved in ASD is just the start for understanding the pathophysiological mechanisms of the disease in patients with this 19q12 syndrome. Can we now identify developmental time periods, brain regions and cell types in which the function of this gene is critical for the pathogenesis of ASD? Here we propose to join the complementary expertise in mouse genetics, neurophysiology and computational biology of three IBDM teams into a multilevel study, from molecule to behavior, to unravel the neurodevelopmental function of TSHZ3 in relationship with ASD. Using three new conditional mouse models that we have generated to delete Tshz3 in the brain in a spatial- and time-controlled manner, we will address the following issues:
1- When is Tshz3 function critical in CPNs, by determining the anatomo-functional and behavioral consequences of its targeted embryonic or post-natal deletion.
2- Where is Tshz3 function critical outside of the cortex, by focusing on Tshz3-expressing striatal cholinergic interneurons.
3- How is the transcription factor TSHZ3 acting, by identifying i) the modules of TSHZ3 target genes required for the proper formation and function of brain circuits and ii) its direct targets within these modules.
Interestingly, our preliminary data suggest that the repertoire of ASD-related behavioral abnormalities linked to Tshz3 deficiency involves defects in distinct components of the corticostriatal circuits, and that the post-natal function of Tshz3 in CPNs is implicated in ASD pathogenesis. Since the viability of Tshz3 mutant neurons is not affected in corticostriatal circuits, this raises the promising issue of rescuing postnatally the ASD phenotype. To do so, we will generate and characterize a conditional rescue mouse model in which Tshz3 expression will be restored after birth in the cerebral cortex of heterozygous Tshz3 mice. We expect that completion of this project will provide new insights on molecular pathways and brain circuits involved in ASD, from neuron specification at embryonic stages to regulation of synaptic function at post-natal stages. If Tshz3-associated dysfunctions can be reversible in mice, comparative analysis of postnatal deletion and postnatal rescue of Tshz3 might further help identifying targets for future therapeutic developments.