Association between SNAP-25 gene polymorphisms and cognition in autism: functional consequences and potential therapeutic strategies

Braida, Daniela; Guerini, Franca Rosa; Ponzoni, Luisa; Corradini, Irene; Astis, Silvia De; Pattini, Linda; Bolognesi, Elisabetta; Benfante, Roberta; Fornasari, Diego; Chiappedi, Matteo; Ghezzo, Alessandro; Clerici, Mario; Matteoli, Michela; Sala, Mariaelvina

doi:10.1038/tp.2014.136

Cited by 78 publications

(60 citation statements)

References 57 publications

(71 reference statements)

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“…It is interesting to note that, in a previous paper, mice heterozygous for SNAP25 , a gene involved in different psychiatric disorders, including ASD, attention deficit hyperactivity disorder and schizophrenia, were impaired in VOR using stationary shapes. However, the decreased discrimination index was recovered by the application of motion.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Interestingly, heterozygote Snap‐25 null mice under certain conditions, such as exposure to prenatal stress, exhibit deficits in social interaction that may be explained by synaptic deficits related to neurotransmission . This highlights a potential role for SNAP‐25 changes in the social recognition deficits observed in spp −/− mice, as SNAP‐25 has also been implicated in other disorders involving social impairment …”

Section: Discussionmentioning

confidence: 99%

“…36,37 This highlights a potential role for SNAP-25 changes in the social recognition deficits observed in spp −/− mice, as SNAP-25 has also been implicated in other disorders involving social impairment. 38 FIGURE 5 Impaired recognition of social novelty in spp −/− mice. A, Example trackplot of a spp −/− mouse during a social preference trial exploring an empty cage or a cage with a mouse inside.…”

Section: Discussionmentioning

confidence: 99%

Single point mutation on the gene encoding dysbindin results in recognition deficits

Chang

Fernando

Yeung

et al. 2018

Genes Brain and Behavior

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The dystrobrevin-binding protein 1 (DTNBP1) gene is a candidate risk factor for schizophrenia and has been associated with cognitive ability in both patient populations and healthy controls. DTNBP1 encodes dysbindin protein, which is localized to synaptic sites and is reduced in the prefrontal cortex and hippocampus of patients with schizophrenia, indicating a potential role in schizophrenia etiology. Most studies of dysbindin function have focused on the sandy (sdy) mice that lack dysbindin protein and have a wide range of abnormalities. In this study, we examined dysbindin salt and pepper (spp) mice that possess a single point mutation on the Dtnbp1 gene predicted to reduce, but not eliminate, dysbindin expression. By western blot analysis, we found that spp homozygous (spp -/-) mutants had reduced dysbindin and synaptosomal-associated protein 25 (SNAP-25) in the prefrontal cortex, but unaltered levels in hippocampus. Behaviorally, spp mutants performed comparably to controls on a wide range of tasks assessing locomotion, anxiety, spatial recognition and working memory. However, spp -/- mice had selective deficits in tasks measuring novel object recognition and social novelty recognition. Our results indicate that reduced dysbindin and SNAP-25 protein in the prefrontal cortex of spp -/- is associated with selective impairments in recognition processing. These spp mice may prove useful as a novel mouse model to study cognitive deficits linked to dysbindin alterations. Our findings also suggest that aspects of recognition memory may be specifically influenced by DTNBP1 single nucleotide polymorphisms or risk haplotypes in humans and this connection should be further investigated.

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“…As model 4 (Figure 5d) shows, miR-3666 can play an "enemy" role to FOXP2 by repressing FOXP1 and removing its inhibitory effect on CNTNAP2 or it may inhibit FOXP1 expression and affect the modulatory roles of FOXP2 that requires FOXP1-FOXP2 dimerization. FOXP2 and miR-3666 can also jointly affect the levels of common targets MET (MET receptor tyrosine kinase), TCF4, SNAP25 (synaptosomal-associated protein of 25 kDa) and PTPN11, which are candidate genes for ASD [103][104][105][106][107]. PAX6 regulation by miR-3666 is not only important to maintain the levels of FOXP2 but also to prevent the development of autism and related disorders, as PAX6 is also a candidate gene for ASD [108].…”

Section: Foxp2 and Mir-3666 May Be Responsible For The Pathogenesis Omentioning

confidence: 99%

Intronic miRNA miR-3666 Modulates its Host Gene FOXP2 Functions in Neurodevelopment and May Contribute to Pathogenesis of Neurological Disorders Schizophrenia and Autism

Islam¹

2017

JABB

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MicroRNAs (miRNAs) are approximately 22-nucleotide-long, non-coding RNAs that bind to complementary mRNAs with inhibitory effect. An intronic miRNA is embedded in a particular gene called its host gene. Our study focuses on the Homo sapiens intronic miRNA-host gene pair, hsa-miR-3666 and FOXP2. Previous report of coexpression of miR-3666 and FOXP2 indicates possible regulation of FOXP2 functions by miR-3666. However, direct correlation has not been shown yet. Therefore, we took a computational approach to determine if and how such modulation occurs. ChIP-seq identified FOXP2 targets and putative miR-3666 targets showed a significant overlap of 574 common target genes. Functional enrichment analysis of common targets revealed over-representation of KEGG pathways and Gene Ontology modules associated with neurodevelopment. These modules, along with further literature mining and proteinprotein interaction analysis of FOXP2 and miR-3666 identified several specific genes associated with neurodevelopment and finally integration of transcriptomic expressions data lead to the selection of four models depicting the mechanisms by which miR-3666 can modulate FOXP2 functions. Model 1 illustrates that during neurodevelopment, miR-3666 can directly modulate the functions of FOXP2 through regulation of common targets, such as IGF1 and EFNB2, whereas model 2 shows miR-3666 can also indirectly modulate FOXP2 functions by considering targets that are not common for the intronic miRNA-host gene pair, for example CDH2 and LMO4. This direct and indirect regulation is necessary for precise spatial and temporal expression of genes during neurodevelopment. Models 3 and 4 exhibit mechanisms in which the interactions of miR-3666 and FOXP2 with target genes contribute to the pathogenesis of schizophrenia and autism respectively. a role in transcriptional activation [7]. FOXP2 hosts the intronic miRNA, miR-3666. Though not much work has been done on miR-3666, its targets have been predicted and deposited in various databases. A few recent experiments have shown the repression activity of miR-3666 on targets such as MET and ZEB1 in thyroid carcinoma and cervical carcinoma cells, respectively [9,10].

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Association between SNAP-25 gene polymorphisms and cognition in autism: functional consequences and potential therapeutic strategies

Cited by 78 publications

References 57 publications

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

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

Single point mutation on the gene encoding dysbindin results in recognition deficits

Intronic miRNA miR-3666 Modulates its Host Gene FOXP2 Functions in Neurodevelopment and May Contribute to Pathogenesis of Neurological Disorders Schizophrenia and Autism

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Association between SNAP-25 gene polymorphisms and cognition in autism: functional consequences and potential therapeutic strategies

Cited by 78 publications

References 57 publications

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

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

Single point mutation on the gene encoding dysbindin results in recognition deficits

Intronic miRNA miR-3666 Modulates its Host Gene FOXP2 Functions in Neurodevelopment and May Contribute to Pathogenesis of Neurological Disorders Schizophrenia and Autism

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

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