Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients

Sadakata, Tetsushi; Washida, Miwa; Iwayama, Yoshimi; Shoji, Shuichi; Sato, Yuichi; Ohkura, Takeyoshi; Katoh‐Semba, Ritsuko; Nakajima, Mizuho; Sekine, Yasuji; Tanaka, Mika; Nakamura, Kazuhiko; Iwata, Yasuhide; Tsuchiya, Kenji J.; Mori, Norio; Detera‐Wadleigh, Sevilla D.; Ichikawa, Hironobu; Itohara, Shigeyoshi; Yoshikawa, Takeo; Furuichi, Teiichi

doi:10.1172/jci29031

Cited by 192 publications

(226 citation statements)

References 60 publications

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“…1, item 7.7). This result, together with abnormalities in Cadps2 knockout mice and rare missense variants in patients 45 , supports a potential role for this positional candidate in disease. Similarly, a de novo loss at 20p13 (including the arginine vasopressin gene, the oxytocin gene and an additional 30 genes 4 ) is intriguing given the associations between the variation in each of the corresponding receptors and ASDs (see later section on association studies) as well as the wellestablished role of both molecules in the modulation of social behaviour.…”

Section: Copy Number Variationsupporting

confidence: 61%

Advances in autism genetics: on the threshold of a new neurobiology

2008

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Autism is a heterogeneous syndrome defined by impairments in three core domains: social interaction, language and range of interests. Recent work has led to the identification of several autism susceptibility genes and an increased appreciation of the contribution of de novo and inherited copy number variation. Promising strategies are also being applied to identify common genetic risk variants. Systems biology approaches, including array-based expression profiling, are poised to provide additional insights into this group of disorders, in which heterogeneity, both genetic and phenotypic, is emerging as a dominant theme.Autistic disorder is the most severe end of a group of neurodevelopmental disorders referred to as autism spectrum disorders (ASDs), which share the common feature of dysfunctional reciprocal social interaction. A meta-analysis of ASD prevalence rates suggests that approximately 37 in 10,000 individuals are affected 1 . ASDs encompass several clinically defined conditions (see BOX 1 and the Diagnostic and Statistical Manual of Mental Disorders), pervasive developmental disorder -not otherwise specified and autistic disorder are the most common, whereas Asperger syndrome appears less frequently. Boys are at increased risk for the ASDs, an effect that becomes even more pronounced in so-called high-functioning cases.A chronological overview of research in the ASDs underscores the short history of genetic work in this area as well as the diversity of the methods used. Before the 1970s, autism was not widely appreciated to have a strong biological basis. Instead, various psychodynamic interpretations, including the role of a cold or aloof style of mothering, were invoked as potential causes. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript co-occurrence of chromosomal disorders and rare syndromes with the ASDs were noted 2 . Subsequent twin and family studies provided additional support for a complex genetic aetiology, but these were limited by the lack of uniform diagnostic criteria. The development of validated diagnostic and assessment tools in the early 1990s, most notably the Autism Diagnostic Interview -Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS), addressed these concerns and these tools have proven crucial to the advancement of international research into the ASDs. This work, in concert with important technical advances, made it possible to carry out the first candidate gene association studies and resequencing efforts in the late 1990s. Whole-genome linkage studies followed, and were used to identify additional loci of potential interest. Although the application of genome-wide techniques to assess copy number variation (CNV) has only just begun 3-5 , these studies have already identified a large number of potentially important novel candidate loci.Thus, in contrast to the complete absence of any biological understanding of the ASDs as recently as 30 years ago, we now know that defined mutations, genetic syndromes and de novo CNV acco...

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Section: Copy Number Variationsupporting

confidence: 61%

Advances in autism genetics: on the threshold of a new neurobiology

2008

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“…14 Each mouse was placed in the center of an open-field apparatus (50 Â 50 Â 40 (H) cm) illuminated by light-emitting diodes (70 lux at the center of the field) and then allowed to move freely for 15 min. Distance traveled (cm) and duration (%) in the center area of the field (30% of the field) were adopted as the indices, and the relevant data were collected every 1 min.…”

Section: Open-field Testmentioning

confidence: 99%

Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities

et al. 2008

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Mutations in SLITRK1 are found in patients with Tourette's syndrome and trichotillomania. SLITRK1 encodes a transmembrane protein containing leucine-rich repeats that is produced predominantly in the nervous system. However, the role of this protein is largely unknown, except that it can modulate neurite outgrowth in vitro. To clarify the role of Slitrk1 in vivo, we developed Slitrk1-knockout mice and analyzed their behavioral and neurochemical phenotypes. Slitrk1-deficient mice exhibited elevated anxiety-like behavior in the elevated plus-maze test as well as increased immobility time in forced swimming and tail suspension tests. Neurochemical analysis revealed that Slitrk1-knockout mice had increased levels of norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylglycol. Administration of clonidine, an a2-adrenergic agonist that is frequently used to treat patients with Tourette's syndrome, attenuated the anxiety-like behavior of Slitrk1-deficient mice in the elevated plusmaze test. These results lead us to conclude that noradrenergic mechanisms are involved in the behavioral abnormalities of Slitrk1-deficient mice. Elevated anxiety due to Slitrk1 dysfunction may contribute to the pathogenesis of neuropsychiatric diseases such as Tourette's syndrome and trichotillomania.

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“…Our previous studies have shown that CAPS2 is involved in the secretion of BDNF in cerebellar granule cells and cerebral cortical neurons (7,8). BDNF plays a critical role in neuronal survival and differentiation and in synaptic development and plasticity (9)(10)(11)(12).…”

mentioning

confidence: 99%

Calcium-dependent activator protein for secretion 2 (CAPS2) promotes BDNF secretion and is critical for the development of GABAergic interneuron network

Shinoda

Sadakata

Nakao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Calcium-dependent activator protein for secretion 2 (CAPS2) is a dense-core vesicle-associated protein that is involved in the secretion of BDNF. BDNF has a pivotal role in neuronal survival and development, including the development of inhibitory neurons and their circuits. However, how CAPS2 affects BDNF secretion and its biological significance in inhibitory neurons are largely unknown. Here we reveal the role of CAPS2 in the regulated secretion of BDNF and show the effect of CAPS2 on the development of hippocampal GABAergic systems. We show that CAPS2 is colocalized with BDNF, both synaptically and extrasynaptically in axons of hippocampal neurons. Overexpression of exogenous CAPS2 in hippocampal neurons of CAPS2-KO mice enhanced depolarization-induced BDNF exocytosis events in terms of kinetics, frequency, and amplitude. We also show that in the CAPS2-KO hippocampus, BDNF secretion is reduced, and GABAergic systems are impaired, including a decreased number of GABAergic neurons and their synapses, a decreased number of synaptic vesicles in inhibitory synapses, and a reduced frequency and amplitude of miniature inhibitory postsynaptic currents. Conversely, excitatory neurons in the CAPS2-KO hippocampus were largely unaffected with respect to field excitatory postsynaptic potentials, miniature excitatory postsynaptic currents, and synapse number and morphology. Moreover, CAPS2-KO mice exhibited several GABA system-associated deficits, including reduced late-phase long-term potentiation at CA3-CA1 synapses, decreased hippocampal theta oscillation frequency, and increased anxiety-like behavior. Collectively, these results suggest that CAPS2 promotes activity-dependent BDNF secretion during the postnatal period that is critical for the development of hippocampal GABAergic networks.dense-core vesicles | brain-derived neurotrophic factor | GABAergic synapse

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Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients

Cited by 192 publications

References 60 publications

Advances in autism genetics: on the threshold of a new neurobiology

Advances in autism genetics: on the threshold of a new neurobiology

Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities

Calcium-dependent activator protein for secretion 2 (CAPS2) promotes BDNF secretion and is critical for the development of GABAergic interneuron network

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