Loss of the imprinted snoRNA mbii-52 leads to increased 5htr2c pre-RNA editing and altered 5HT2CR-mediated behaviour

Doe, Christine M.; Relkovic, Dinko; Garfield, Alastair S.; Dalley, Jeffrey W.; Theobald, David E. H.; Humby, Trevor; Wilkinson, Lawrence S.; Isles, Anthony R

doi:10.1093/hmg/ddp137

Cited by 152 publications

(153 citation statements)

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“…In this regard, it is notable that a 5-CSRTT phenotype has been recently reported in a mouse model with altered 5-HT 2C receptor function. Mice engineered to recapitulate features of the PWS (PWS-IC þ / À mice) were found to have increased 5-HT 2C receptor editing, leading to the expression of less active receptor isoforms (Doe et al, 2009). Interestingly, similar to our findings, PWS-IC þ / À mice required significantly more sessions to reach the baseline criterion in the 5-CSRTT.…”

Section: Discussionsupporting

confidence: 83%

“…A potential role for 5-HT 2C receptors in attention is also supported by the analysis of genetically modified mice modeling the Prader-Willi syndrome (PWS). These animals express less active 5-HT 2C receptor isoforms and display an attention deficit in the 5-CSRTT (Doe et al, 2009;Relkovic et al, 2010). In addition, 5-HT 2C receptors have been implicated in behavioral flexibility, which is commonly examined by administering reversal learning tasks that assess the ability of animals to shift responding from a previously learned to new stimulus-reward contingencies (Boulougouris et al, 2008;Boulougouris and Robbins, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Impact of Serotonin (5-HT)2C Receptors On Executive Control Processes

Pennanen

Hart

et al. 2012

Neuropsychopharmacol

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Although the serotonin (5-hydroxytryptamine, 5-HT) neurotransmitter system has been implicated in modulating executive control processes such as attention, response inhibition, and behavioral flexibility, the contributions of particular serotonin receptors remain unclear. Here, using operant-based behavioral paradigms, we demonstrate that mice with genetically ablated 5-HT 2C receptors (2CKO mice) display deficits in executive functions. 2CKO mice were impaired in the acquisition of a visuospatial attention task as assessed in the 5-choice serial reaction time task (5-CSRTT). In this task, 2CKO mice exhibited marked impairment of attentional processes, with normal response inhibition. We assessed dynamic changes in neurotransmitter levels within the nucleus accumbens (NAc) by in vivo microdialysis in task-performing animals. Extracellular dopamine concentrations were elevated in the NAc of 2CKO mice during task performance, indicating that 5-HT 2C receptors impact dopamine homeostasis during a visuospatial attention task. These findings raise the possibility that disinhibition of mesolimbic dopamine pathways contributes to impaired attention and perturbed task performance in 2CKO mice. Additionally, in a spatial reversal learning task, 2CKO mice failed to improve their performance over a series of reversals, indicating that intact 5-HT 2C receptor signaling is required to accurately respond to repeated changes in reward contingencies. In contrast to the 2CKO phenotype in the 5-CSRTT, wild-type mice treated with the 5-HT 2C receptor antagonist SB242084 exhibited diminished response inhibition, suggesting differing effects of acute pharmacological blockade and constitutive loss of 5-HT 2C receptor activity. Altogether, these findings provide insights into the serotonergic regulation of executive control processes and suggest that impaired 5-HT 2C receptor signaling during development may predispose to executive function disorders.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Impact of Serotonin (5-HT)2C Receptors On Executive Control Processes

Pennanen

Hart

et al. 2012

Neuropsychopharmacol

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“…The involvement of 5-HT 2C receptors in this and other forms of behavioral inhibition also brings into play a number of molecular mechanisms able to modify the efficacy of 5-HT 2C receptor signaling in the brain. For example, the role of genes such as Snord115, which can modify 5-HT 2C receptor function via effects on posttranscriptional modifications of 5-HT 2C receptor pre-RNA (Kishore and Stamm, 2006), and which we have shown using mouse models in previous work, can influence aspects of response control (Doe et al, 2009). We anticipate that, in allowing exploitation of the advanced genomic and genetic tractability of mice, the development of the mouse SSRTT will be of significant utility in furthering the generation of viable translational models, and new therapeutic targets, for disorders where failures of behavioral inhibition are prominent.…”

Section: Discussionmentioning

confidence: 96%

A Novel Translational Assay of Response Inhibition and Impulsivity: Effects of Prefrontal Cortex Lesions, Drugs Used in ADHD, and Serotonin 2C Receptor Antagonism

Humby

Eddy

Good

et al. 2013

Neuropsychopharmacol

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Animal models are making an increasing contribution to our understanding of the psychology and brain mechanisms underlying behavioral inhibition and impulsivity. The aim here was to develop, for the first time, a mouse analog of the stop-signal reaction time task with high translational validity in order to be able to exploit this species in genetic and molecular investigations of impulsive behaviors. Cohorts of mice were trained to nose-poke to presentations of visual stimuli. Control of responding was manipulated by altering the onset of an auditory 'stop-signal' during the go response. The anticipated systematic changes in action cancellation were observed as stopping was made more difficult by placing the stop-signal closer to the execution of the action. Excitotoxic lesions of medial prefrontal cortex resulted in impaired stopping, while the clinically effective drugs methylphenidate and atomoxetine enhanced stopping abilities. The specific 5-HT 2C receptor antagonist SB242084 also led to enhanced response control in this task. We conclude that stop-signal reaction time task performance can be successfully modeled in mice and is sensitive to prefrontal cortex dysfunction and drug treatments in a qualitatively similar manner to humans and previous rat models. Additionally, using this model we show novel and highly discrete effects of 5-HT 2C receptor antagonism that suggest manipulation of 5-HT 2C receptor function may be of use in correcting maladaptive impulsive behaviors and provide further evidence for dissociable contributions of serotonergic transmission to response control.

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“…The targeted site within the 5-HT 2C R pre-mRNA is subject to A-to-I RNA editing and is also juxtaposed to an alternative splice site (Canton et al 1996;Burns et al 1997;Wang et al 2000b). In the past, several groups have reported the involvement of MBII-52 in regulation of editing or splicing of the 5-HT 2C R pre-mRNA (Vitali et al 2005; Kishore and Stamm 2006;Doe et al 2009). In these studies it has been noted that MBII-52 snoRNA transcripts are extremely abundant in mouse brain, compared to canonical snoRNAs (Hüttenhofer et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Identification of novel ribonucleo-protein complexes from the brain-specific snoRNA MBII-52

Soeno¹,

Taya²,

Stasyk³

et al. 2010

RNA

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Small nucleolar RNAs (snoRNAs) guide nucleotide modifications within ribosomal RNAs or spliceosomal RNAs by base-pairing to complementary regions within their RNA targets. The brain-specific snoRNA MBII-52 lacks such a complementarity to rRNAs or snRNAs, but instead has been reported to target the serotonin receptor 2C pre-mRNA, thereby regulating pre-mRNA editing and/or alternative splicing. To understand how the MBII-52 snoRNA might be involved in these regulatory processes, we isolated the MBII-52 snoRNP from total mouse brain by an antisense RNA affinity purification approach. Surprisingly, by mass spectrometry we identified 17 novel candidates for MBII-52 snoRNA binding proteins, which previously had not been reported to be associated with canonical snoRNAs. Among these, Nucleolin and ELAVL1 proteins were confirmed to independently and directly interact with the MBII-52 snoRNA by coimmunoprecipitation. Our findings suggest that the MBII-52 snoRNA assembles into novel RNA-protein complexes, distinct from canonical snoRNPs.

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Loss of the imprinted snoRNA mbii-52 leads to increased 5htr2c pre-RNA editing and altered 5HT2CR-mediated behaviour

Cited by 152 publications

References 42 publications

Impact of Serotonin (5-HT)2C Receptors On Executive Control Processes

Impact of Serotonin (5-HT)2C Receptors On Executive Control Processes

A Novel Translational Assay of Response Inhibition and Impulsivity: Effects of Prefrontal Cortex Lesions, Drugs Used in ADHD, and Serotonin 2C Receptor Antagonism

Identification of novel ribonucleo-protein complexes from the brain-specific snoRNA MBII-52

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