SHANK genes in autism: Defining therapeutic targets

Mossa, Adele; Giona, Federica; Pagano, Jessica; Sala, Carlo; Verpelli, Chiara

doi:10.1016/j.pnpbp.2017.11.019

Cited by 32 publications

(37 citation statements)

References 91 publications

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“…In addition, the immunostaining result indicates that Shank3-positive punctate structures are observed on the dendrites of GAD67-positive GABAergic neurons in cultured hippocampal neurons. Given that Shank3 is an important component of the postsynaptic density at excitatory synapses (Sheng and Kim, 2000 ; Sheng and Sala, 2001 ; Boeckers et al, 2002 ; Sheng and Hoogenraad, 2007 ; Grabrucker et al, 2011 ; Sheng and Kim, 2011 ; Jiang and Ehlers, 2013 ; Sala et al, 2015 ; Monteiro and Feng, 2017 ; Mossa et al, 2017 ), the lack of Shank3 in dorsolateral striatal neurons may suppress normal development and maturation of the postsynaptic density, dendritic spines, and excitatory synapses. In addition, previous studies have reported a strong decrease in dendritic spine density in dorsal striatal neurons in Shank3B −/− mice (Peca et al, 2011 ), further suggesting that the decreased mEPSC frequency may be a consequence of postsynaptic changes.…”

Section: Discussionmentioning

confidence: 99%

“…Shank represents a family of postsynaptic scaffolding proteins with three known members: Shank1/ProSAP3, Shank2/ProSAP1 and Shank3/ProSAP2 (Sheng and Kim, 2000 ; Sheng and Sala, 2001 ; Boeckers et al, 2002 ; Sheng and Hoogenraad, 2007 ; Grabrucker et al, 2011 ; Sheng and Kim, 2011 ; Jiang and Ehlers, 2013 ; Sala et al, 2015 ; Monteiro and Feng, 2017 ; Mossa et al, 2017 ). Shank proteins interact with many other synaptic proteins and are known to regulate excitatory synapse assembly as well as excitatory synaptic transmission and plasticity.…”

Section: Introductionmentioning

confidence: 99%

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GABA Neuronal Deletion of Shank3 Exons 14–16 in Mice Suppresses Striatal Excitatory Synaptic Input and Induces Social and Locomotor Abnormalities

Yoo

Cho

Lee

et al. 2018

Front. Cell. Neurosci.

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Shank3 is an excitatory postsynaptic scaffolding protein implicated in multiple brain disorders, including autism spectrum disorders (ASD) and Phelan-McDermid syndrome (PMS). Although previous neurobiological studies on Shank3 and Shank3-mutant mice have revealed diverse roles of Shank3 in the regulation of synaptic, neuronal and brain functions, whether Shank3 expression in specific cell types distinctly contributes to mouse phenotypes remains largely unclear. In the present study, we generated two Shank3-mutant mouse lines (exons 14–16) carrying global and GABA neuron-specific deletions and characterized their electrophysiological and behavioral phenotypes. These mouse lines show similar decreases in excitatory synaptic input onto dorsolateral striatal neurons. In addition, the abnormal social and locomotor behaviors observed in global Shank3-mutant mice are strongly mimicked by GABA neuron-specific Shank3-mutant mice, whereas the repetitive and anxiety-like behaviors are only partially mimicked. These results suggest that GABAergic Shank3 (exons 14–16) deletion has strong influences on striatal excitatory synaptic transmission and social and locomotor behaviors in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

GABA Neuronal Deletion of Shank3 Exons 14–16 in Mice Suppresses Striatal Excitatory Synaptic Input and Induces Social and Locomotor Abnormalities

Yoo

Cho

Lee

et al. 2018

Front. Cell. Neurosci.

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“…Various CNS disorders comorbid with ARBs have strong genetic determinants, including neuroligin (NLGN), GABA A-receptor β3 gene (GABRB3), methyl-CpG-binding protein 2 (MeCP2), the fragile X mental retardation (FMR1), contactin-associated protein-like 2 (Cntnap2), SHANK family, tuberous sclerosis complex 1 (TSC1), neurexin 1a (NRXN1) [50][51][52] and dopamine D3 receptor genes (DRD3) [53,54]. Neuroligin genes (e.g., NLGN3) modulate dopaminergic signaling in ventral striatum [55], and mouse knockouts in NLGN3 display robust motor stereotypies [55].…”

Section: Introductionmentioning

confidence: 99%

Abnormal repetitive behaviors in zebrafish and their relevance to human brain disorders

Zabegalov

Khatsko

Lakstygal

et al. 2019

Behavioural Brain Research

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Abnormal repetitive behaviors (ARBs) are a prominent symptom of numerous human brain disorders and are commonly seen in rodent models. As rodent studies of ARBs continue to dominate the field, mounting evidence suggests that zebrafish (Danio rerio) also display ARB-like phenotypes and may therefore be a novel model organism for ARB research. In addition to practical research advantages, zebrafish share high genetic and physiological homology to humans and rodents, including multiple ARB-related genes and stereotypic behaviors relevant to ARB. Here, we discuss a wide spectrum of stereotypic repetitive behaviors in zebrafish, data on their genetic and pharmacological modulation, and the overall translational relevance of fish ARBs to modeling human brain disorders. Overall, the zebrafish is rapidly emerging as a new promising model to study ARBs and their underlying mechanisms.

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“…Within the huge amount of proteins involved in ASD, SHANK family proteins (SHANK1, SHANK2, SHANK3) have emerged as promising candidates for modeling ASD in mice. A strong genetic evidence showed molecular defects of SHANK protein in patients with ASD . SHANK3 is essential for building the structure of dendritic spines, and its haploinsufficiency is strongly associated with the Phelan McDermid syndrome, a form of ID often associated with ASD and characterized by delayed or absent speech, neonatal hypotonia and attention deficits .…”

Section: Introductionmentioning

confidence: 99%

“…A strong genetic evidence showed molecular defects of SHANK protein in patients with ASD. 22,23 SHANK3 is essential for building the structure of dendritic spines, and its haploinsufficiency is strongly associated with the Phelan McDermid syndrome, a form of ID often associated with ASD and characterized by delayed or absent speech, neonatal hypotonia and attention deficits. 24 A decrease in glutamatergic transmission and in LTP, a neuronal hypertrophy and a reduction in spine density were observed in animal models of SHANK3 haploinsufficiency.…”

mentioning

confidence: 99%

Different attentional dysfunctions in eEF2K^−/−, IL1RAPL1^−/− and SHANK3Δ11^−/− mice

Ponzoni

Sala

Verpelli

et al. 2019

Genes Brain and Behavior

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A common feature of several psychiatric disorders is the attentional impairment. eEF2K −/−, IL1RAPL1 −/− and SHANK3Δ11 −/− mice were used as animal models consistently linked to changes in synaptic plasticity, learning and memory. All knockout (KO) mice and their corresponding littermates were submitted to the novel object recognition (NOR) and visual object recognition (VOR) tasks. In the NOR, eEF2K−/− mice exhibited a normal performance in terms of mean discrimination index, while SHANK3Δ11−/− and IL1RAPL1 −/− mice were impaired when a delay of 2 and 24 hours was introduced. Surprisingly, when submitted to VOR, where the two objects were replaced with two shapes delivered from two iPods, all the mutant mice performed worse than those in the NOR. In VOR, the application of motion to different shapes, to increase attention, improved performance in eEF2K −/− and IL1RAPL1 −/− but not in SHANK3Δ11 −/− mice. In SHANK3Δ11 −/− mice, attentional deficit was also present even if different motions were applied to the same shapes or when these mice were repeatedly exposed for 5 days to the context. Behavioral analysis showed that eEF2K−/− and IL1RAPL1 −/− mice had a good flexibility tested in the T‐maze. eEF2K−/− showed normal self‐grooming. On the basis of previous literature data indicating that SHANK3Δ11 −/− showed impaired flexibility and reduced sociability, we identified in this genotype the most exhaustive model showing all the core symptoms of autism spectrum disorder including a heavy visual attention deficit. These findings show the importance of VOR to identify mouse models of autism.

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SHANK genes in autism: Defining therapeutic targets

Cited by 32 publications

References 91 publications

GABA Neuronal Deletion of Shank3 Exons 14–16 in Mice Suppresses Striatal Excitatory Synaptic Input and Induces Social and Locomotor Abnormalities

GABA Neuronal Deletion of Shank3 Exons 14–16 in Mice Suppresses Striatal Excitatory Synaptic Input and Induces Social and Locomotor Abnormalities

Abnormal repetitive behaviors in zebrafish and their relevance to human brain disorders

Different attentional dysfunctions in eEF2K^−/−, IL1RAPL1^−/− and SHANK3Δ11^−/− mice

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SHANK genes in autism: Defining therapeutic targets

Cited by 32 publications

References 91 publications

GABA Neuronal Deletion of Shank3 Exons 14–16 in Mice Suppresses Striatal Excitatory Synaptic Input and Induces Social and Locomotor Abnormalities

GABA Neuronal Deletion of Shank3 Exons 14–16 in Mice Suppresses Striatal Excitatory Synaptic Input and Induces Social and Locomotor Abnormalities

Abnormal repetitive behaviors in zebrafish and their relevance to human brain disorders

Different attentional dysfunctions in eEF2K−/−, IL1RAPL1−/− and SHANK3Δ11−/− mice

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Product

Resources

About

Different attentional dysfunctions in eEF2K^−/−, IL1RAPL1^−/− and SHANK3Δ11^−/− mice