Serotonin2A/C receptors mediate the aggressive phenotype of TLX gene knockout mice

Juárez, Pablo; Valdovinos, Maria G.; May, Michael; Lloyd, Blair P.; Couppis, Maria H.; Kennedy, Craig H.

doi:10.1016/j.bbr.2013.07.044

Cited by 21 publications

(21 citation statements)

References 30 publications

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“…Adult Tlx -mutant brains also show severe deficits in active neurogenic regions such as reduced hippocampal DG size, significantly expanded lateral ventricles, and smaller olfactory bulbs [12, 13]. The mutation of mouse Tlx results in hyperactivity and extremely aggressive behavior suggesting a potential role for TLX in human neurological disorders [14]. In support of this hypothesis, mutations in the regulatory regions of the human Tlx gene have been positively correlated with bipolar disorder.…”

Section: Introductionmentioning

confidence: 99%

TLX: A master regulator for neural stem cell maintenance and neurogenesis

Islam¹,

Zhang²

2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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The orphan nuclear receptor TLX, also known as NR2E1, is an essential regulator of neural stem cell (NSC) self-renewal, maintenance, and neurogenesis. In vertebrates, TLX is specifically localized to the neurogenic regions of the forebrain and retina throughout development and adulthood. TLX regulates the expression of genes involved in multiple pathways, such as the cell cycle, DNA replication, and cell adhesion. These roles are primarily performed through the transcriptional repression or activation of downstream target genes. Emerging evidence suggests the misregulation of TLX might play a role in the onset and progression of human neurological disorders making this factor an ideal therapeutic target. Here, we review the current understanding of TLX function, expression, regulation, and activity significant to NSC maintenance, adult neurogenesis, and brain plasticity.

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Section: Introductionmentioning

confidence: 99%

TLX: A master regulator for neural stem cell maintenance and neurogenesis

Islam¹,

Zhang²

2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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“…In Tlx-mutant mice, the normal retinal cell types are specified early, but the number of cells in each layer later progressively decreases, ending as malformation of the vascular system [50]. Studies of conditional depletion of Tlx that will save visual function suggested that blindness at least partially is related to the cognitive defect and other behavioural abnormalities observed in these mice [43, 67, 68]. Additionally, Tlx-mutant animals suffer from defects in retinal vasculature, reaffirming the role for Tlx in the assembly of fibronectin matrices secreted by proangiogenic astrocytes [64].…”

Section: Introductionmentioning

confidence: 99%

“…Prior to resident-intruder challenges, the aggressive behaviour of Tlx-mutant mice was diminished by a selective 5-HT 2A/C receptor antagonist. This suggests that this 5-HT 2 receptor is involved in the mechanism behind aggression [68]. As for the basis of conditioned emotional responses, inactivation of the amygdala will prevent fear conditioning to both cue and context, whereas hippocampal dysfunction prevents fear conditioning to context only [74, 75].…”

Section: Introductionmentioning

confidence: 99%

TLX—Its Emerging Role for Neurogenesis in Health and Disease

Sobhan

Funa

2016

Mol Neurobiol

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The orphan nuclear receptor TLX, also called NR2E1, is a factor important in the regulation of neural stem cell (NSC) self-renewal, neurogenesis, and maintenance. As a transcription factor, TLX is vital for the expression of genes implicated in neurogenesis, such as DNA replication, cell cycle, adhesion and migration. It acts by way of repressing or activating target genes, as well as controlling protein-protein interactions. Growing evidence suggests that dysregulated TLX acts in the initiation and progression of human disorders of the nervous system. This review describes recent knowledge about TLX expression, structure, targets, and biological functions, relevant to maintaining adult neural stem cells related to both neuropsychiatric conditions and certain nervous system tumours.

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“…Recent evidence suggests that both the 5‐HT 2C R antagonist and 5‐HT 2C R inverse agonist mitigate aggressive behavior. The 5‐HT 2A/C R antagonist decreased aggressive behavior (Juárez et al., ; Umukoro et al., ). Furthermore, S32212, a combined 5‐HT 2C R inverse agonist that also possesses 5‐HT 2A R antagonist properties, suppressed aggressive behavior in mice (Dekeyne et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, 5-HT 2C R is activated in the shock-aggression mouse (Ennis et al, 2003). Juárez et al (2013) showed that 5-HT 2C R can mediate the aggressive phenotype of TLX gene knockout mice. The RNA splicing and editing modulation of 5-HT 2C R function is relevant to aggression in VGV (full edited VGV isoform of 5-HT 2C R) mice (Martin et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

5‐HT_2CR antagonist/5‐HT_2CR inverse agonist recovered the increased isolation‐induced aggressive behavior of BALB/c mice mediated by ADAR1 (p110) expression and Htr2c RNA editing

Xue

et al. 2018

Brain and Behavior

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IntroductionSocial isolation enhances the aggressive behavior of animals, but the detailed mechanism remains unclear. Epigenetic studies have suggested that Htr2c RNA editing is closely related to aggressive behavior. This study aims to obtain a fundamental understanding of how social isolation impacts adenosine deaminase acting on RNA 1 (ADAR1, RNA editing enzyme) and Htr2c RNA editing, leading to aggressive behavior, and explore the effective solutions for the recovery of this behavior.MethodsWe evaluated 21‐day‐old BALB/c mice with and without isolation for aggressive behavior using a resident‐intruder test. Immune‐reactivity and protein expression of ADAR1 (p110) were measured using immunohistochemistry and Western blotting. Htr2c RNA editing was evaluated using pyrosequencing. In addition, the 5‐HT 2C R antagonist SB243213/5‐HT 2C R inverse agonist SB206553 was used to treat the isolated mice, and the performance of both treatments on the behavior, ADAR1 (p110) expression, and Htr2c RNA editing in isolated mice was examined.ResultsBoth the protein expression and immune‐reactivity of ADAR1 (p110) in the amygdala decreased, but the percentage of Htr2c RNA editing at A and B sites of amygdala only showed a moderate increase in isolated BALB/c mice with enhanced aggressive behavior compared to the age‐matched group‐housed BALB/c mice. Additionally, treatment with the 5‐HT 2C R antagonist SB243213/5‐HT 2C R inverse agonist SB206553 recovered the enhanced aggressive behavior of isolated mice and returned the protein expression and immune‐reactivity of ADAR1 (p110) back to the normal level. Moreover, compared to the age‐matched isolated mice treated with physiological saline, isolated mice treated with 5‐HT 2C R inverse agonist SB206553 showed a lower percentage of Htr2c RNA editing at both A and B sites, and the same result occurred in isolated mice treated with 5‐HT 2C R antagonist SB243213 at B site of Htr2c RNA editing.ConclusionsThe 5‐HT 2C R antagonist SB243213/5‐HT 2C R inverse agonist SB206553 recovered increased aggressive behavior of isolated BALB/c mice mediated by ADAR1 (p110) expression and Htr2c RNA editing.

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Serotonin2A/C receptors mediate the aggressive phenotype of TLX gene knockout mice

Cited by 21 publications

References 30 publications

TLX: A master regulator for neural stem cell maintenance and neurogenesis

TLX: A master regulator for neural stem cell maintenance and neurogenesis

TLX—Its Emerging Role for Neurogenesis in Health and Disease

5‐HT_2CR antagonist/5‐HT_2CR inverse agonist recovered the increased isolation‐induced aggressive behavior of BALB/c mice mediated by ADAR1 (p110) expression and Htr2c RNA editing

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Serotonin2A/C receptors mediate the aggressive phenotype of TLX gene knockout mice

Cited by 21 publications

References 30 publications

TLX: A master regulator for neural stem cell maintenance and neurogenesis

TLX: A master regulator for neural stem cell maintenance and neurogenesis

TLX—Its Emerging Role for Neurogenesis in Health and Disease

5‐HT2CR antagonist/5‐HT2CR inverse agonist recovered the increased isolation‐induced aggressive behavior of BALB/c mice mediated by ADAR1 (p110) expression and Htr2c RNA editing

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5‐HT_2CR antagonist/5‐HT_2CR inverse agonist recovered the increased isolation‐induced aggressive behavior of BALB/c mice mediated by ADAR1 (p110) expression and Htr2c RNA editing