Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenerci abnormalities
Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan. Molecular Psychiatry
(Impact Factor: 14.5).
10/2008; 15(2):177-84. DOI: 10.1038/mp.2008.97
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 alpha2-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 plus-maze 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.
Available from: Marc E Lavoie
- "Parallèlement, l'expression du SLITRK1 a été confirmée dans les circuits striataux et corticaux, ce qui concorderait avec les régions impliquées dans la pathologie du SGT (Stillman et al., 2009). Un modèle animal a démontré une carence du gène SLITRK1 et une altération du phénotype associé à l'activité noradrénergique dans le SGT (Katayama et al., 2010). Cependant, l'expression du gène SLITRK1 dans le SGT demeure hypothétique étant donné que d'autres recherches n'ont pas été en mesure de reproduire ces résultats chez l'humain (Scharf et al., 2008). "
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ABSTRACT: Tics are defined as involuntary and repetitive contractions of related groups of squelettal muscles. Their frequency can be exacerbated in certain situations or diminished in others. Chronic tics or the Gilles de la Tourette Syndrome (GTS) may be accompanied by concomitant disorders related to impulsivity. If one knows that the impulsivity variable can be found in a large majority of GTS cases, very few studies have attempted to document its frequency or intensity. Over the past decade, knowledge of the neuropsychology of GTS and the mechanisms underlying impulsivity has progressed rapidly. The current review of the literature, will describe the biological bases of this syndrome and problems of impulsivity in patients with GTS.
- "Currently, genetic animal models have not exhibited the main characteristic of TS; i.e., motor tics. Rather, most animal models can successfully produce a decrease in locomotion (SLITRK1 and HDC models) (Katayama et al. 2010; Kubota et al. 2002), increased twitching (D1CT-7 model) (Nordstrom and Burton, 2002), or TS comorbid symptoms such as OCB [SAPAP3, D1CT-7, DAT, and HDC (following amphetamine injection) models] (Berridge et al. 2005; Campbell et al. 1999; Castellan Baldan et al. 2014; Welch et al. 2007), anxiety (SLITRK1 and SAPAP3 models) (Katayama et al. 2010; Welch et al. 2007), and hyperactivity (D1CT-7 and nonfunctional D3 receptor models) (Accili et al. 1996; Campbell et al. 1999). "
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ABSTRACT: Tourette syndrome (TS) is a common childhood-onset disorder characterized by motor and vocal tics that are typically accompanied by a multitude of comorbid symptoms. Pharmacological treatment options are limited, which has led to the exploration of deep brain stimulation (DBS) as a possible treatment for severe cases. Multiple lines of evidence have linked TS with abnormalities in the motor and limbic cortico-basal ganglia (CBG) pathways. Neurophysiological data have only recently started to slowly accumulate from multiple sources: noninvasive imaging and electrophysiological techniques, invasive electrophysiological recordings in TS patients undergoing DBS implantation surgery and animal models of the disorder. These converging sources point to system level physiological changes throughout the CBG pathway including both general altered baseline neuronal activity patterns and specific tic related activity. DBS has been applied to different regions along the motor and limbic pathways, primarily to the globus pallidus internus, thalamic nuclei and nucleus accumbens. In line with the findings that also draw on the more abundant application of DBS to Parkinson's disease, this stimulation is assumed to result in changes in the neuronal firing patterns and the passage of information through the stimulated nucleus. We present an overview of recent experimental findings on abnormal neuronal activity associated with TS and the changes in this activity following DBS. These findings are then discussed in the context of current models of CBG function in the normal state, during TS, and finally in the wider context of DBS in CBG-related disorders.
Copyright © 2015, Journal of Neurophysiology.
Available from: Thomas V Fernandez
- "In addition, Kajiwara, Buxbaum, and Grice (2009) reported that the regulation of neurite outgrowth , as described by Aruga and Mikoshiba (2003) is mediated by binding to 14-3-3 molecules. Finally, Katayama et al. (2010) reported increased noradrenergic neurotransmission in a SLITRK1 mouse knockout that showed manifested an anxiety phenotype. A particularly interesting result reported recently by Shmelkov et al. (2010) was the observation of excessive grooming, responsive to agents that treat obsessive compulsive disorder in a mouse knockout of the closely related molecule, SLITRK5. "
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ABSTRACT: Georges Gilles de la Tourette, in describing the syndrome that now bears his name, observed that the condition aggregated within families. Over the last three decades, numerous studies have confirmed this observation, and demonstrated that familial clustering is in part due to genetic factors. Recent studies are beginning to provide clues about the underlying genetic mechanisms important for the manifestation of some cases of Tourette Disorder (TD). Evidence has come from different study designs, such as nuclear families, twins, multigenerational families, and case-control samples, together examining the broad spectrum of genetic variation including cytogenetic abnormalities, copy number variants, genome-wide association of common variants, and sequencing studies targeting rare and/or de novo variation. Each of these classes of genetic variation holds promise for identifying the causative genes and biological pathways contributing to this paradigmatic neuropsychiatric disorder.
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