Excessive self-grooming, gene dysregulation and imbalance between the striosome and matrix compartments in the striatum of Shank3 mutant mice

Abstract

Autism is characterized by atypical social communication and stereotyped behaviors. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are detected in 1–2% of patients with autism and intellectual disability, but the mechanisms underpinning the symptoms remain largely unknown. Here, we characterized the behavior of Shank3Δ11/Δ11 mice from 3 to 12 months of age. We observed decreased locomotor activity, increased stereotyped self-grooming and modification of 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 (DEGs). DEGs were identified mainly in the striatum and were associated with synaptic transmission (e.g., Grm2, Dlgap1), G-protein-signaling pathways (e.g., Gnal, Prkcg1, and Camk2g), as well as excitation/inhibition balance (e.g., Gad2). Downregulated and upregulated genes were enriched in the gene clusters of medium-sized spiny neurons expressing the dopamine 1 (D1-MSN) and the dopamine 2 receptor (D2-MSN), respectively. Several DEGs (Cnr1, Gnal, Gad2, and Drd4) were reported as striosome markers. By studying the distribution of the glutamate decarboxylase GAD65, encoded by Gad2, we showed that the striosome compartment of Shank3Δ11/Δ11 mice was enlarged and displayed much higher expression of GAD65 compared to wild-type mice. Altogether, these results indicate altered gene expression in the striatum of Shank3-deficient mice and strongly suggest, for the first time, that the excessive self-grooming of these mice is related to an imbalance in the striatal striosome and matrix compartments.

Cilia loss on distinct neuron populations differentially alters cocaine-induced locomotion and reward

“…In contrast to acute responses, locomotor sensitization in Gad2:IFT88 KO mice was altered, though only at the lowest dose. GAD2 is expressed in both Drd1+ and Drd2+ medium spiny neurons in the rodent striatum (Ferhat et al, 2023). Activation of Drd1+ neurons is known to promote locomotion (Freeze et al, 2013;Kravitz et al, 2010), whereas Drd2+ neuron activation and DRD2 agonism can inhibit locomotion (Barrozo et al, 2015;Durieux et al, 2009;Ford, 2014).…”

Striatal insights: a cellular and molecular perspective on repetitive behaviors in pathology

“…In another mouse model in which Shank3 exon 11 is deleted (Shank3 Δ11/Δ11 ), authors report striatal transcriptional alterations in both dSPNs and iSPNs with downregulated genes mainly expressed by dSPNs and upregulated genes expressed by iSPNs ( Ferhat et al, 2023 ). Running a functional analysis, among the protein functions primarily affected by transcriptional alterations there are synaptic transmission and G-protein activity.…”

“…Concerning ASD, reports in mouse models and human postmortem brain tissue show that striatal compartments exhibit pathological alterations ( Kuo and Liu, 2017 , 2020 ). Moreover, a recent study reported a correlation between the level of self-grooming and increased striatal expression of several genes, including glutamic acid decarboxylase 2 ( Gad2 ; Ferhat et al, 2023 ), encoding GAD65, which present preferentially in axonal terminals for synthesis of GABA for vesicle release ( Esclapez et al, 1994 ; Tian et al, 1999 ). Notably, Shank3 Δ11/Δ11 and mice with a complete lack of all SHANK3 isoforms displayed an enlargement of the compartment formed by striosomes which displayed over-expressed GAD65.…”

“…Notably, Shank3 Δ11/Δ11 and mice with a complete lack of all SHANK3 isoforms displayed an enlargement of the compartment formed by striosomes which displayed over-expressed GAD65. Authors suggest that signaling imbalance between the striosome and matrix compartments of the striatum in SHANK3-deficient mice underlie these repetitive behaviors ( Ferhat et al, 2023 ). These data go in line with the previous study reporting that aberrant development of striosomal and matrix compartments of striatum leads to dysfunction in corticostriatal connectivity, leading to repetitive behaviors in mouse model of ASD ( Kuo and Liu, 2017 ).…”

Putamen volume as a predictor of repetitive and restricted behaviors and interests related intensity in autism

“…and in autism(Langhen et al, 2014, van Rooij et al, 2018, Mc Kinnon et al, 2019, Ferhat et al, 2023. Including the putamen, the basal ganglia play important roles in regulating repetitive behaviors (notably in autism) in association with the hippocampus, the hypothalamus, but also other neuroanatomical structures of the limbic system (including the amygdala) (Gandhi et al, 2021).…”