Absence of familiarity triggers hallmarks of autism in mouse model through aberrant tail-of-striatum and prelimbic cortex signaling

Krüttner, Sebastian; Falasconi, Antonio; Valbuena, Sergio; Galimberti, Ivan; Bouwmeester, Tewis; Arber, Silvia; Caroni, Pico

doi:10.1016/j.neuron.2022.02.001

Cited by 21 publications

(19 citation statements)

References 72 publications

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“…This is in line with a recent study showing that inclusion of “running wheels, igloos, toys, tunnels, a maze, and nesting material” in a large home cage both reduces anxiety and improves social affiliation in the BTBR strain 54 . A similar effect was also observed for the Shank3 ΔC/ΔC mouse model of ASD 55 . In this model enriched environment rescued ASD‐like phenotype of the mutant, including the dependence of novel context recognition on activation of the dopaminergic prelimbic‐tail‐of‐striatum pathway.…”

Section: Discussionsupporting

confidence: 91%

Social deficits in BTBR T+ Itpr3tf/J mice vary with ecological validity of the test

Winiarski

Kondrakiewicz

et al. 2022

Genes Brain and Behavior

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Translational value of mouse models of neuropsychiatric disorders depends heavily on the accuracy with which they replicate symptoms observed in the human population. In mouse models of autism spectrum disorder (ASD) these include, among others, social affiliation, and communication deficits as well as impairments in understanding and perception of others. Most studies addressing these issues in the BTBR T+ Itpr3tf/J mouse, an idiopathic model of ASD, were based on short dyadic interactions of often non‐familiar partners placed in a novel environment. In such stressful and variable conditions, the reproducibility of the phenotype was low. Here, we compared physical conditions and the degree of habituation of mice at the time of testing in the three chambered social affiliation task, as well as parameters used to measure social deficits and found that both the level of stress and human bias profoundly affect the results of the test. To minimize these effects, we tested social preference and network dynamics in mice group‐housed in the Eco‐HAB system. This automated recording allowed for long‐lasting monitoring of differences in social repertoire (including interest in social stimuli) in BTBR T+ Itpr3tf/J and normosocial c57BL/6J mice. With these observations we further validate the BTBR T+ Itpr3tf/J mouse as a model for ASD, but at the same time emphasize the need for more ecological testing of social behavior within all constructs of the Systems for Social Processes domain (as defined by the Research Domain Criteria framework).

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Section: Discussionsupporting

confidence: 91%

Social deficits in BTBR T+ Itpr3tf/J mice vary with ecological validity of the test

Winiarski

Kondrakiewicz

et al. 2022

Genes Brain and Behavior

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“…Increased self-grooming might reflect a response to stressful conditions, which might vary from one individual to another (difference in susceptibility and/or exposure to stressful conditions). Such increased reactivity to novel or stressful conditions is reminiscent of what is observed in patients and deserves further systematic testing in the different Shank3 mutant models 33 .…”

Section: Discussionmentioning

confidence: 87%

Excessive self-grooming, gene dysregulation and imbalance between the striosome and matrix compartments in the striatum ofShank3mutant mice

Ferhat

Biton

Verpy

et al. 2022

Preprint

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Autism spectrum disorders (ASD) are characterised by atypical social communication and stereotyped behaviours. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are detected in 1-2% of patients with ASD and intellectual disability (ID), but the mechanisms underpinning the symptoms remain largely unknown. Here, we characterized the behaviour of Shank3 mutant mice deleted for exon 11 (Shank3Δ11/Δ11) from three to twelve months of age. We observed decreased locomotor activity, increased stereotyped self-grooming and atypical socio-sexual interaction compared to wild-type littermates. We then used RNAseq on four brain regions of the same animals to identify differentially expressed genes (DEG). DEGs were identified mainly in the striatum and were associated with synaptic transmission (e.g. Grm2, Dlgap1), G-protein-signalling pathways (e.g. Gnal, Prkcg1, and Camk2g), as well as excitation/inhibition balance (e.g. Gad2). Downregulated and upregulated genes were respectively enriched in the gene clusters of medium-sized spiny neurons expressing the dopamine 1 (D1-MSN) and the dopamine 2 receptor (D2-MSN). Moreover, expression of DEGs reported as striosome markers within the striatum (Cnr1, Gnal1, Gad2, and Drd4) were positively correlated with excessive self-grooming. Finally, we showed that the striosome compartment of Shank3Δ11/Δ11 mice was enlarged and displayed higher expression of GAD65 compared to wild-type mice. Altogether, these results shed light on a possible role of the striosomes/matrix imbalance in excessive self-grooming in Shank3Δ11/Δ11 mice. Such striatal alterations could be present in a subgroup of patients with ASD and ID and could open the way to new therapeutic approaches.

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“…Dysfunctions in fronto-striatal brain circuits have been characterized as responsible for excessive grooming found as stereotypies in Sapap3 mouse model (44). Engagement in social interaction was shown to depend on the activity in prelimbic cortex (PreL)-to-Tail-of-Striatum (TS) projection neurons in wild-type mice and was restored in Shank3 C/C mice by the chemogenetic activation of PreL/TS projection (45).…”

Section: Discussionmentioning

confidence: 99%

“…This test is a species-typical behaviour that is responsive to many factors like hippocampal function, anxiety, depression or obsessive-compulsive disorder (45,46).…”

Section: Marble Burying Testmentioning

confidence: 99%

AUTS2 gene dosage affects synaptic AMPA receptors via a local dendritic spine AUTS2-TTC3-AKT-mTORC1 signaling dysfunction

Lepagnol-Bestel

Duchon

Viard

et al. 2022

Preprint

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The Human 1.2-MbAUTS2locus on chromosome 7q11.22 encodes a 1259-aa full-length protein, and a 711-aa C-terminal isoform. Functions of these AUTS2 proteins are only partly known. The major traits found in patients displaying AUTS2 locus mutations are Intellectual Disabilities, microcephaly attention deficit hyperactivity disorder (ADHD) (54%), and autistic traits. Furthermore,AUTS2common variants were recently found associated to alcohol consumption and dyslexia using GWAS approaches. Auts2 localizes mainly in cell nuclei. We evidenced by super-resolution that Auts2 is present in dendritic spines. Auts2 interacts with Ttc3, the Akt2 E3 ligase, and negatively regulates Akt2 ubiquitination. Auts2 haploinsufficiency affects Akt/mTorc1 pathway with a decrease in AMPA and NMDA receptor subunits and in synaptic currents. Akt2 injection in postsynaptic neurons is sufficient to reverse changes in synaptic currents generated by Auts2 haploinsufficiency. Using chromosome engineering based on targeted meiotic recombination, we generated two mouse models with Auts2 locus deletion and duplication. Deleted Auts2 locus mice display stereotypies (rearing), perseveration and abnormal recognition memory. Duplicated Auts2 locus mice display similar perseveration and abnormal recognition memory but also a decrease in cued and contextual fear memory. Gene dosage induce changes in brain sub-region neuronal networks. In the thalamo-lateral amygdala pathway linked to cued fear memory, we found synaptic impairments linked to AMPA receptors, with a specific decrease in pAKT/total AKT ratio in duplicated Auts2 mice. Altogether, our study thereby provides a novel mechanistic and potentially therapeutic understanding of synaptic AKT/mTORC1 deregulated signaling and its related behavioral and cognitive phenotypes.

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Absence of familiarity triggers hallmarks of autism in mouse model through aberrant tail-of-striatum and prelimbic cortex signaling

Cited by 21 publications

References 72 publications

Social deficits in BTBR T+ Itpr3tf/J mice vary with ecological validity of the test

Social deficits in BTBR T+ Itpr3tf/J mice vary with ecological validity of the test

Excessive self-grooming, gene dysregulation and imbalance between the striosome and matrix compartments in the striatum ofShank3mutant mice

AUTS2 gene dosage affects synaptic AMPA receptors via a local dendritic spine AUTS2-TTC3-AKT-mTORC1 signaling dysfunction

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