Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors

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 Tshz3flox/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.

Developmental deficits of MGE-derived interneurons in the Cntnap2 knockout mouse model of autism spectrum disorder

“…Disruption of cholinergic interneurons (CINs) in the striatum generate network and behavioral modifications significant to ASD ( Rapanelli et al, 2017a ; Caubit et al, 2022 ). Yet, how developing CINs are impacted in ASD has been poorly explored.…”

“…Further study is required to decipher the mechanisms underlying the involvement of specific striatal CINs, which are known to support the pathophysiology of ASD ( Caubit et al, 2022 ), and how changes in cell number and positioning-although transitory-influence other striatal interneurons and output neurons, either directly or by compensatory mechanisms, and the establishment of functional neuronal assemblies within the striatum. Indeed, any alterations in developing interneuron function is expected to alter the excitation-inhibition balance and, overall striatal activity, to ultimately impact activity-dependent mechanisms such as perinatal network oscillations that are fundamental to build functional circuitries ( Dehorter et al, 2012 ).…”

“…Indeed, Cntnap2 is expressed in the MGE progenitors cells in humans (Satterstrom et al, 2020), and in future sub-pallial cholinergic and GABAergic neurons (Shi et al, 2021), suggesting that potential therapeutic interventions could be conducted from embryonic stages to rectify the altered developmental trajectory in ASD, but also a range of neurodevelopmental disorders such as schizophrenia, intellectual disability, dyslexia, epilepsy and attention-deficit hyperactivity disorder (Rodenas-Cuadrado et al, 2014;Poot, 2015). Disruption of cholinergic interneurons (CINs) in the striatum generate network and behavioral modifications significant to ASD (Rapanelli et al, 2017a;Caubit et al, 2022). Yet, how developing CINs are impacted in ASD has been poorly explored.…”

Altered striosome-matrix distribution and activity of striatal cholinergic interneurons in a model of autism-linked repetitive behaviors

“…Here we addressed this issue in the context of ASD. We previously identified TSHZ3 (teashirt zinc-finger homeobox family member 3, also known as ZFP537 ) as an ASD-related gene, and provided evidence that cortical projection neurons and SCINs are main determinants of the ASD-like behavioral abnormalities linked to Tshz3 deletion in mouse models (Caubit et al, 2021; Caubit et al, 2016; Caubit et al, 2022). TSHZ3 is a transcription factor regulating the expression of numerous genes involved in brain development and functioning (Caubit et al, 2021; Caubit et al, 2016; Chabbert et al, 2019; Kang et al, 2011).…”

“…In the striatum, TSHZ3 is not expressed in SSPNs but in virtually all SCINs, which represent more than 90% of the TSHZ3-expressing cells in this structure. In contrast, TSHZ3 is not expressed or is expressed in a low proportion of neurons in the other main cholinergic systems of the brain (Caubit et al, 2022). Conditional deletion (cKO) of Tshz3 in cortical projection neurons ( Emx1-cKO mice) or in SCINs ( Chat-cKO mice) does not modify the number of these neurons but alters, respectively, their synaptic function and their electrophysiological features.…”