Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors - Archive ouverte HAL Access content directly
Journal Articles Translational Psychiatry Year : 2022

Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors

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Abstract

We previously linked TSHZ3 haploinsufficiency to autism spectrum disorder (ASD) and showed that embryonic or postnatal Tshz3 deletion in mice results in behavioral traits relevant to the two core domains of ASD, namely social interaction deficits and repetitive behaviors. Here, we provide evidence that cortical projection neurons (CPNs) and striatal cholinergic interneurons (SCINs) are two main and complementary players in the TSHZ3-linked ASD syndrome. In the cerebral cortex, TSHZ3 is expressed in CPNs and in a proportion of GABAergic interneurons, but not in cholinergic interneurons or glial cells. In the striatum, TSHZ3 is expressed in all SCINs, while its expression is absent or partial in the other main brain cholinergic systems. We then characterized two new conditional knockout (cKO) models generated by crossing Tshz3 flox/flox with Emx1-Cre ( Emx1-cKO ) or Chat-Cre ( Chat-cKO ) mice to decipher the respective role of CPNs and SCINs. Emx1-cKO mice show altered excitatory synaptic transmission onto CPNs and impaired plasticity at corticostriatal synapses, with neither cortical neuron loss nor abnormal layer distribution. These animals present social interaction deficits but no repetitive patterns of behavior. Chat-cKO mice exhibit no loss of SCINs but changes in the electrophysiological properties of these interneurons, associated with repetitive patterns of behavior without social interaction deficits. Therefore, dysfunction in either CPNs or SCINs segregates with a distinct ASD behavioral trait. These findings provide novel insights onto the implication of the corticostriatal circuitry in ASD by revealing an unexpected neuronal dichotomy in the biological background of the two core behavioral domains of this disorder.
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Dates and versions

hal-03819114 , version 1 (18-10-2022)

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Xavier Caubit, Paolo Gubellini, Pierre L. Roubertoux, Michèle Carlier, Jordan Molitor, et al.. Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors. Translational Psychiatry, 2022, 12 (1), pp.106. ⟨10.1038/s41398-022-01865-6⟩. ⟨hal-03819114⟩
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