Shank2/3 double knockout-based screening of cortical subregions links the retrosplenial area to the loss of social memory in autism spectrum disorders

Garrido, Débora; Beretta, Stefania; Grabrucker, Stefanie; Bauer, Helen Friedericke; Bayer, David; Sala, Carlo; Verpelli, Chiara; Roselli, Francesco; Bockmann, Juergen; Proepper, Christian; Catanese, Alberto; Boeckers, Tobias M.

doi:10.1038/s41380-022-01756-8

Cited by 15 publications

(12 citation statements)

References 80 publications

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“…Notably this dysregulation leads to significant downregulation of the corresponding proteins, thus possibly mimicking the loss-of-function effect observed in ASD samples harbouring inactivating mutations in these genes. For instance, the simultaneous downregulation of both Shank2 and Shank3 proteins was recently shown to impair social memory [ 71 ], a feature strictly associated with autism. impairment.…”

Section: Discussionmentioning

confidence: 99%

Fetal exposure to valproic acid dysregulates the expression of autism-linked genes in the developing cerebellum

et al. 2023

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Autism spectrum disorder (ASD) includes a set of highly heritable neurodevelopmental syndromes characterized by social and communication impairment, repetitive behaviour, and intellectual disability. Although mutations in multiple genes have been associated to ASD, most patients lack detectable genetic alterations. For this reason, environmental factors are commonly thought to also contribute to ASD aetiology. Transcriptome analyses have revealed that autistic brains possess distinct gene expression signatures, whose elucidation can provide insights about the mechanisms underlying the effects of ASD-causing genetic and environmental factors. Herein, we have identified a coordinated and temporally regulated programme of gene expression in the post-natal development of cerebellum, a brain area whose defects are strongly associated with ASD. Notably, this cerebellar developmental programme is significantly enriched in ASD-linked genes. Clustering analyses highlighted six different patterns of gene expression modulated during cerebellar development, with most of them being enriched in functional processes that are frequently dysregulated in ASD. By using the valproic acid mouse model of ASD, we found that ASD-linked genes are dysregulated in the developing cerebellum of ASD-like mice, a defect that correlates with impaired social behaviour and altered cerebellar cortical morphology. Moreover, changes in transcript levels were reflected in aberrant protein expression, indicating the functional relevance of these alterations. Thus, our work uncovers a complex ASD-related transcriptional programme regulated during cerebellar development and highlight genes whose expression is dysregulated in this brain area of an ASD mouse model.

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Section: Discussionmentioning

confidence: 99%

Fetal exposure to valproic acid dysregulates the expression of autism-linked genes in the developing cerebellum

et al. 2023

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“…In fact, functional studies in model organisms (e.g., in Shank ko mice) usually rely on a homozygous situation in order to detect a phenotype [57][58][59], despite the fact that SHANK mutations in human patients are always heterozygous. In two recent studies, even double knockout mouse lines (deleting a total of four Shank allels) have been analysed to more clearly assess the function of Shank proteins in synaptic function and autism pathology [60,61].…”

Section: Discussionmentioning

confidence: 99%

Structural deficits in key domains of Shank2 lead to alterations in postsynaptic nanoclusters and to a neurodevelopmental disorder in humans

et al. 2022

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Postsynaptic scaffold proteins such as Shank, PSD-95, Homer and SAPAP/GKAP family members establish the postsynaptic density of glutamatergic synapses through a dense network of molecular interactions. Mutations in SHANK genes are associated with neurodevelopmental disorders including autism and intellectual disability. However, no SHANK missense mutations have been described which interfere with the key functions of Shank proteins believed to be central for synapse formation, such as GKAP binding via the PDZ domain, or Zn2+-dependent multimerization of the SAM domain. We identify two individuals with a neurodevelopmental disorder carrying de novo missense mutations in SHANK2. The p.G643R variant distorts the binding pocket for GKAP in the Shank2 PDZ domain and prevents interaction with Thr(−2) in the canonical PDZ ligand motif of GKAP. The p.L1800W variant severely delays the kinetics of Zn2+-dependent polymerization of the Shank2-SAM domain. Structural analysis shows that Trp1800 dislodges one histidine crucial for Zn2+ binding. The resulting conformational changes block the stacking of helical polymers of SAM domains into sheets through side-by-side contacts, which is a hallmark of Shank proteins, thereby disrupting the highly cooperative assembly process induced by Zn2+. Both variants reduce the postsynaptic targeting of Shank2 in primary cultured neurons and alter glutamatergic synaptic transmission. Super-resolution microscopy shows that both mutants interfere with the formation of postsynaptic nanoclusters. Our data indicate that both the PDZ- and the SAM-mediated interactions of Shank2 contribute to the compaction of postsynaptic protein complexes into nanoclusters, and that deficiencies in this process interfere with normal brain development in humans.

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“…Previous reports have associated the RSC region with autistic-like phenotypes in mice 28,29 . Based on these reports, we attempted to alleviate the phenotypic defects in Srcap +/mice by expressing Satb2 specifically in RSC.…”

Section: Rsc-specific Expression Of Satb2 Reversed Social Deficits In...mentioning

confidence: 93%

SrcapHaploinsufficiency Induced Autistic-Like Behaviors in Mice through Disruption ofSatb2Expression

Qiu

Ding

Shi

et al. 2023

Preprint

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Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with significant genetic predispositions. Among these, loss-of-function mutations of the chromatin remodeling gene SRCAP have been identified in individuals with ASD, but their pathogenic mechanisms have yet to be fully elucidated. In this study, we established a germline mutant mouse model harboring a heterozygous frameshift mutation in the Srcap gene (Srcap+/-). The Srcap+/- mice exhibited notable impairments in social novelty, repetitive and stereotyped behaviors, anxiety, and learning and memory deficits. We observed a decreased number of parvalbumin (PV)-expressing neurons in their retrosplenial cortex (RSC) and dentate gyrus (DG). Furthermore, abnormalities in dendritic structure, synaptic density, and synaptic transmission were noted in the DG of Srcap+/- mice. RNA sequencing revealed that the expression of 27 genes, implicated in ASD, was dysregulated in the Srcap haploinsufficiency mice. Among these genes, we found that Srcap haploinsufficiency resulted in decreased Satb2 expression due to diminished H2A.z-binding within the promoter region of Satb2. Remarkably, intervention through retro-orbital injection of AAV vectors expressing Satb2 in newborn Srcap+/- mice reversed autistic-like behaviors and developmental defects in the RSC and DG regions. Similarly, in adolescent Srcap+/- mice, stereotactic injection of AAV expressing Satb2 into the RSC ameliorated deficits in social novelty. Collectively, these findings highlight the crucial role of the Srcap in neurodevelopment by regulating Satb2 expression, particularly impacting the development of RSC and DG regions.

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Shank2/3 double knockout-based screening of cortical subregions links the retrosplenial area to the loss of social memory in autism spectrum disorders

Cited by 15 publications

References 80 publications

Fetal exposure to valproic acid dysregulates the expression of autism-linked genes in the developing cerebellum

Fetal exposure to valproic acid dysregulates the expression of autism-linked genes in the developing cerebellum

Structural deficits in key domains of Shank2 lead to alterations in postsynaptic nanoclusters and to a neurodevelopmental disorder in humans

SrcapHaploinsufficiency Induced Autistic-Like Behaviors in Mice through Disruption ofSatb2Expression

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