AUTS2 regulation of synapses for proper synaptic inputs and social communication

Hori, Kei; Yamashiro, Kunihiko; Nagai, Taku; Shan, Wei; Egusa, Saki F.; Shimaoka, Kazumi; Go, Yasuhiro; Tatsumoto, Shoji; Yamada, Mitsuyo; Shiraishi, Reika; Kanno, Kouta; Miyashita, Satoshi; Sakamoto, Asami; Abe, Manabu; Sakimura, Kenji; Sone, Masaki; Sohya, Kazuhiro; Yamada, Kiyofumi; Hoshino, Mikio

doi:10.1101/871012

Cited by 3 publications

(14 citation statements)

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“…A similar phenotype was observed in Auts2 cKO cerebellum; dendritic spine numbers as well as excitatory inputs were increased without affecting inhibitory inputs in PCs. Because most of the dendritic spines and excitatory inputs we observed should correspond to PF synapses, AUTS2 may also function to restrict the number of PF synapses via its action in the cell nuclei, as was reported for the telencephalon (Hori et al, 2019).…”

Section: Cacna1asupporting

confidence: 56%

“…Consistent with this, downregulation of Auts2 in PCs leads to the enhancement of PF-dependent excitatory neurotransmission. We previously showed that AUTS2 restricts the number of excitatory synapses without affecting that of inhibitory synapses in the telencephalon (Hori et al, 2019). This function is elicited by nuclear AUTS2, because nuclear-localizing but not cytoplasmic-localizing AUTS2 is able to rescue the excessive spine phenotype in cultured hippocampal neurons from Auts2 mutant mice.…”

Section: Cacna1amentioning

confidence: 98%

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AUTS2 Governs Cerebellar Development, Purkinje Cell Maturation, Motor Function and Social Communication

Yamashiro

Hori

Lai

et al. 2020

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Autism susceptibility candidate 2 (AUTS2), a risk gene for autism spectrum disorders (ASDs), is implicated in telencephalon development. Because AUTS2 is also expressed in the cerebellum where defects have been linked to ASDs, we investigated AUTS2 functions in the cerebellum. AUTS2 is specifically localized in Purkinje cells (PCs) and Golgi cells during postnatal development. Auts2 conditional knockout (cKO) mice exhibited smaller and deformed cerebella containing immature-shaped PCs with reduced expression of Cacna1a.Auts2 cKO and knock-down experiments implicated AUTS2 participation in elimination and translocation of climbing fiber synapses, and restriction of parallel fiber synapse numbers.Auts2 cKO mice exhibited behavioral impairments in motor learning and vocal communications. Because Cacna1a is known to regulate synapse development in PCs, it suggests that AUTS2 is required for PC maturation to elicit normal development of PC synapses and thus the impairment of AUTS2 may cause cerebellar dysfunction related to psychiatric illnesses such as ASDs.

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Section: Cacna1asupporting

confidence: 56%

Section: Cacna1amentioning

confidence: 98%

AUTS2 Governs Cerebellar Development, Purkinje Cell Maturation, Motor Function and Social Communication

Yamashiro

Hori

Lai

et al. 2020

Preprint

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“…To obtain a deeper understanding, we first took a conventional approach by categorizing all syllables into twelve types ( Fig. 2C ) based on their spectrotemporal patterns, according to previous reports (Hori et al, 2020; Kikusui et al, 2011; Scattoni et al, 2008). The USV acoustic features of the twelve syllable types are shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Advanced paternal age diversifies individual trajectories of vocalization patterns in neonatal mice

Mai

Kimura

Hori

et al. 2019

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25Autism Spectrum Disorder (ASD) is one of the neurodevelopmental disorders and 26 characterized with persistent impairments in social communication (including verbal 27 and nonverbal communication) and repetitive behavior together with various 28 comorbid symptoms. Epidemiological studies suggest a significant association 29 between advanced paternal age and incidence of ASD in offspring, which has been 30 modeled in rodents. However, how paternal aging makes an impact on the offspring's 31 early communicative behavior, especially at the individual level, has not been 32 addressed. Here we systematically analyzed postnatal development of vocal 33 communication of pups by measuring ultrasonic vocalization (USV) induced by 34 maternal separation that is considered to correspond to baby's cry, an earliest verbal 35 communication in human. Maternal separation-induced USV of each offspring 36 derived from young (3 months) or aged (>12 months) father was individually 37 measured for 5 minutes at postnatal day 3 (P3), P6, P9, and P12. We classified USV 38 syllables into twelve types according to Scattoni's classification with minor 39 modifications, and analyzed duration, maximum frequency, maximum amplitude and 40 interval of each syllable. Compared between the two groups, the offspring derived 41 from aged fathers emitted the syllables with less number, shorter duration, different 42 syllable components and less diversity. From an individual perspective, offspring 43 derived from young father showed a developmental convergence in vocal 44 communication, while those from aged fathers exhibited atypical developmental 45 patterns. Taken together, we showed for the first time a significant influence of 46 paternal aging on early vocal development with qualitative and quantitative aspects in 47 50 Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by 51 two core symptoms; i.e., social interaction impairment (including verbal and 52 nonverbal communication deficits) and repetitive behavior [1][2][3] . In most cases, the 53 exact etiology of ASD remains unclear, although researchers believe that genetic, 54 environmental and epigenetic factors are involved in the neuropathology of ASD [4][5][6] . 55In recent years, epidemiological studies repeatedly suggest a significant association 56 between paternal aging and a risk of ASD in offspring. Compared with the children of 57 young fathers, the children were more likely to be diagnosed ASD if their fathers 58 were older [7][8][9][10] . Thus, paternal aging can be worth to be focused as one of the 59 non-genetic mechanisms leading to ASD. 60 61In the new criteria of DSM-5, the communication and social interaction parts are 62 combined into one, i.e., "Social/Communication Deficits". This modification 63 emphasizes the importance of the social communication domain in ASD in early 64 infancy. Human infant crying is an innate social communication [11, 12] , which has a 65 natural peak in frequency of approximately 2.5 hours of crying per day at aroun...

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“…Primary hippocampal cultures were prepared as previously described (Hori et al., 2020) with some modifications. 12 mm glasses were coated with 0.1 mg/ml PDL (Sigma‐Aldrich) a day before seeding.…”

Section: Methodsmentioning

confidence: 99%

“…It is known that mutations in important genes for nervous system development cause a variety of NDDs. For example, autism susceptibility candidate 2 ( AUTS2 ) participates in neuronal differentiation and migration, neurite extension and synaptogenesis, but mutations in that gene cause a wide spectrum of disorders, such as schizophrenia, depression, ASD, ADHD, ID/DD and language disability (Hori & Hoshino, 2017; Hori et al., 2014, 2020). Given that DSCAML1 is also involved in various steps in the nervous system development, we suspected that mutations in DSCAML1 may be related not only to epilepsy but also other NDDs.…”

Section: Introductionmentioning

confidence: 99%

Potential involvement of DSCAML1 mutations in neurodevelopmental disorders

et al. 2021

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The molecular mechanisms underlying neurodevelopmental disorders (NDDs) remain unclear. We previously identified Down syndrome cell adhesion molecule like 1 (Dscaml1) as a responsible gene for Ihara epileptic rat (IER), a rat model for human NDDs with epilepsy. However, the relationship between NDDs and DSCAML1 in humans is still elusive. In this study, we screened databases of autism spectrum disorders (ASD), intellectual disability (ID)/developmental disorders (DD) and schizophrenia for genomic mutations in human DSCAML1. We then performed in silico analyses to estimate the potential damage to the mutated DSCAML1 proteins and chose three representative mutations (DSCAML1C729R, DSCAML1R1685* and DSCAML1K2108Nfs*37), which lacked a cysteine residue in the seventh Ig domain, the intracellular region and the C‐terminal PDZ‐binding motif, respectively. In overexpression experiments in a cell line, DSCAML1C729R lost its mature N‐glycosylation, whereas DSCAML1K2108Nfs*37 was abnormally degraded via proteasome‐dependent protein degradation. Furthermore, in primary hippocampal neurons, the ability of the wild‐type DSCAML1 to regulate the number of synapses was lost with all mutant proteins. These results provide insight into understanding the roles of the domains in the DSCAML1 protein and further suggest that these mutations cause functional changes, albeit through different mechanisms, that likely affect the pathophysiology of NDDs.

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AUTS2 regulation of synapses for proper synaptic inputs and social communication

Cited by 3 publications

References 64 publications

AUTS2 Governs Cerebellar Development, Purkinje Cell Maturation, Motor Function and Social Communication

AUTS2 Governs Cerebellar Development, Purkinje Cell Maturation, Motor Function and Social Communication

Advanced paternal age diversifies individual trajectories of vocalization patterns in neonatal mice

Potential involvement of DSCAML1 mutations in neurodevelopmental disorders

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