Impaired cliff avoidance reaction in dopamine transporter knockout mice

Yamashita, Motoyasu; Sakakibara, Yasufumi; Hall, F. Scott; Numachi, Yohtaro; Yoshida, Sumiko; Kobayashi, Hideaki; Uchiumi, Osamu; Uhl, George R.; Kasahara, Yoshiyuki; Sora, Ichiro

doi:10.1007/s00213-013-3009-9

Cited by 61 publications

(52 citation statements)

References 44 publications

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“…The repetitive peering down behavior of Brinp3 −/− mice has been previously reported in the dopamine transporter (DAT knock-out) mouse model for ADHD as the “cliff avoidance reaction” (Yamashita et al, 2013), which could indicate that changes in synaptic dopamine levels may contribute to this behavior in Brinp3 −/− mice. Another explanation could be changes in levels of the stress-response neurotransmitter norepinephrine in the Brinp3 −/− mice, as Brinp3 expression correlates with changes in norepinephrine levels (Goddard et al, 2010; Karoly et al, 2012).…”

Section: Discussionmentioning

confidence: 81%

Mice Lacking Brinp2 or Brinp3, or Both, Exhibit Behaviors Consistent with Neurodevelopmental Disorders

Berkowicz

Featherby

Whisstock

et al. 2016

Front. Behav. Neurosci.

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Background: Brinps 1–3, and Astrotactins (Astn) 1 and 2, are members of the Membrane Attack Complex/Perforin (MACPF) superfamily that are predominantly expressed in the mammalian brain during development. Genetic variation at the human BRINP2/ASTN1 and BRINP1/ASTN2 loci has been implicated in neurodevelopmental disorders. We, and others, have previously shown that Brinp1−/− mice exhibit behavior reminiscent of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD).Method: We created Brinp2−/− mice and Brinp3−/− mice via the Cre-mediated LoxP system to investigate the effect of gene deletion on anatomy and behavior. Additionally, Brinp2−/−Brinp3−/− double knock-out mice were generated by interbreeding Brinp2−/− and Brinp3−/− mice. Genomic validation was carried out for each knock-out line, followed by histological, weight and behavioral examination. Brinp1−/−Brinp2−/−Brinp3−/− triple knock-out mice were also generated by crossing Brinp2/3 double knock-out mice with previously generated Brinp1−/− mice, and examined by weight and histological analysis.Results: Brinp2−/− and Brinp3−/− mice differ in their behavior: Brinp2−/− mice are hyperactive, whereas Brinp3−/− mice exhibit marked changes in anxiety-response on the elevated plus maze. Brinp3−/− mice also show evidence of altered sociability. Both Brinp2−/− and Brinp3−/− mice have normal short-term memory, olfactory responses, pre-pulse inhibition, and motor learning. The double knock-out mice show behaviors of Brinp2−/− and Brinp3−/− mice, without evidence of new or exacerbated phenotypes.Conclusion: Brinp3 is important in moderation of anxiety, with potential relevance to anxiety disorders. Brinp2 dysfunction resulting in hyperactivity may be relevant to the association of ADHD with chromosome locus 1q25.2. Brinp2−/− and Brinp3−/− genes do not compensate in the mammalian brain and likely have distinct molecular or cell-type specific functions.

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Section: Discussionmentioning

confidence: 81%

Mice Lacking Brinp2 or Brinp3, or Both, Exhibit Behaviors Consistent with Neurodevelopmental Disorders

Berkowicz

Featherby

Whisstock

et al. 2016

Front. Behav. Neurosci.

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“…Mice were 1.5 months old when tested. Cliff avoidance was assayed as previously described (Yamashita et al, 2013). …”

Section: Methodsmentioning

confidence: 99%

The Familial Dysautonomia disease gene,Ikbkap/Elp1, is required in the developing and adult central nervous system

Chaverra

George

Mergy

et al. 2017

Disease Models &Amp; Mechanisms

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Hereditary sensory and autonomic neuropathies (HSANs) are a genetically and clinically diverse group of disorders defined by peripheral nervous system (PNS) dysfunction. HSAN type III, known as familial dysautonomia (FD), results from a single base mutation in the gene IKBKAP that encodes a scaffolding unit (ELP1) for a multi-subunit complex known as Elongator. Since mutations in other Elongator subunits (ELP2 to ELP4) are associated with central nervous system (CNS) disorders, the goal of this study was to investigate a potential requirement for Ikbkap in the CNS of mice. The sensory and autonomic pathophysiology of FD is fatal, with the majority of patients dying by age 40. While signs and pathology of FD have been noted in the CNS, the clinical and research focus has been on the sensory and autonomic dysfunction, and no genetic model studies have investigated the requirement for Ikbkap in the CNS. Here, we report, using a novel mouse line in which Ikbkap is deleted solely in the nervous system, that not only is Ikbkap widely expressed in the embryonic and adult CNS, but its deletion perturbs both the development of cortical neurons and their survival in adulthood. Primary cilia in embryonic cortical apical progenitors and motile cilia in adult ependymal cells are reduced in number and disorganized. Furthermore, we report that, in the adult CNS, both autonomic and non-autonomic neuronal populations require Ikbkap for survival, including spinal motor and cortical neurons. In addition, the mice developed kyphoscoliosis, an FD hallmark, indicating its neuropathic etiology. Ultimately, these perturbations manifest in a developmental and progressive neurodegenerative condition that includes impairments in learning and memory. Collectively, these data reveal an essential function for Ikbkap that extends beyond the peripheral nervous system to CNS development and function. With the identification of discrete CNS cell types and structures that depend on Ikbkap, novel strategies to thwart the progressive demise of CNS neurons in FD can be developed.

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“…Cliff avoidance reaction (CAR) test (Fromer et al, 2014) was assessed using a round wooden platform (diameter, 20 cm), supported by a wooden rod (height, 50 cm;Matsuoka et al, 2005;Yamashita et al, 2013). The test was initiated by placing an animal on a platform.…”

Section: Methodsmentioning

confidence: 99%

“…In the CAR test, a test for impulsivity (Matsuoka et al, 2005;Kuroda et al, 2011;Yamashita et al, 2013), AC1ϩ mice are more active than WT mice and examined the cliff more frequently than WT mice. This risk-taking behavior led to more falls from the platform.…”

Section: Ac1؉ Mice Are Hyperactive and Lack Behavioral Inhibitionmentioning

confidence: 99%

Overexpression of the Type 1 Adenylyl Cyclase in the Forebrain Leads to Deficits of Behavioral Inhibition

et al. 2015

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The type 1 adenylyl cyclase (AC1) is an activity-dependent, calcium-stimulated adenylyl cyclase expressed in the nervous system that is implicated in memory formation. We examined the locomotor activity, and impulsive and social behaviors of AC1ϩ mice, a transgenic mouse strain overexpressing AC1 in the forebrain. Here we report that AC1ϩ mice exhibit hyperactive behaviors and demonstrate increased impulsivity and reduced sociability. In contrast, AC1 and AC8 double knock-out mice are hypoactive, and exhibit increased sociability and reduced impulsivity. Interestingly, the hyperactivity of AC1ϩ mice can be corrected by valproate, a mood-stabilizing drug. These data indicate that increased expression of AC1 in the forebrain leads to deficits in behavioral inhibition.

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Impaired cliff avoidance reaction in dopamine transporter knockout mice

Cited by 61 publications

References 44 publications

Mice Lacking Brinp2 or Brinp3, or Both, Exhibit Behaviors Consistent with Neurodevelopmental Disorders

Mice Lacking Brinp2 or Brinp3, or Both, Exhibit Behaviors Consistent with Neurodevelopmental Disorders

The Familial Dysautonomia disease gene,Ikbkap/Elp1, is required in the developing and adult central nervous system

Overexpression of the Type 1 Adenylyl Cyclase in the Forebrain Leads to Deficits of Behavioral Inhibition

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