Targeting tryptophan hydroxylase 2 in affective disorder

Попова, Н. К.; Куликов, А. В.

doi:10.1517/14728222.2010.524208

Cited by 31 publications

(17 citation statements)

References 131 publications

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“…Although not shown in the present study, insufficient tph2 or lack of serotonin has been shown to lead to mood disorders such as depression [30], schizophrenia [31] and neurodegeneration such as Alzheimer’s dementia [32], [33]. Our mRNA expression study clearly demonstrated that unloading-induced tph2 deficiency is prevented by pre-application of knee loading.…”

Section: Discussionsupporting

confidence: 39%

Physical Weight Loading Induces Expression of Tryptophan Hydroxylase 2 in the Brain Stem

et al. 2014

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Sustaining brain serotonin is essential in mental health. Physical activities can attenuate mental problems by enhancing serotonin signaling. However, such activity is not always possible in disabled individuals or patients with dementia. Knee loading, a form of physical activity, has been found to mimic effects of voluntary exercise. Focusing on serotonergic signaling, we addressed a question: Does local mechanical loading to the skeleton elevate expression of tryptophan hydroxylase 2 (tph2) that is a rate-limiting enzyme for brain serotonin? A 5 min knee loading was applied to mice using 1 N force at 5 Hz for 1,500 cycles. A 5-min treadmill running was used as an exercise (positive) control, and a 90-min tail suspension was used as a stress (negative) control. Expression of tph2 was determined 30 min – 2 h in three brain regions ––frontal cortex (FC), ventromedial hypothalamus (VMH), and brain stem (BS). We demonstrated for the first time that knee loading and treadmill exercise upregulated the mRNA level of tph2 in the BS, while tail suspension downregulated it. The protein level of tph2 in the BS was also upregulated by knee loading and downregulated by tail suspension. Furthermore, the downregulation of tph2 mRNA by tail suspension can be partially suppressed by pre-application of knee loading. The expression of tph2 in the FC and VMH was not significantly altered with knee loading. In this study we provided evidence that peripheral mechanical loading can activate central tph2 expression, suggesting that physical cues may mediate tph2-cathalyzed serotonergic signaling in the brain.

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Section: Discussionsupporting

confidence: 39%

Physical Weight Loading Induces Expression of Tryptophan Hydroxylase 2 in the Brain Stem

et al. 2014

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“…This member of the aminoacid hydroxylase family catalyzes the formation of the direct 5-HT precursor, 5-hydroxy-tryptophan (5-HTP) from tryptophan (Walther et al, 2003). Multiple noncoding or loss-of-function polymorphisms in the TPH2 gene have been identified as potential genetic risk factors for several psychiatric illnesses, including bipolar disorder, major depression, attention deficit hyperactivity disorder (ADHD), and schizophrenia (Popova and Kulikov, 2010;Russo et al, 2009;Waider et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation

Del’Guidice

Lemay

Lemasson

et al. 2013

Neuropsychopharmacol

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Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. However, little is known about the impact of Tph2 gene variants on cognition. Mice expressing a human TPH2 variant (Tph2-KI) were used to investigate cognitive consequences of TPH2 loss of function and pharmacological treatments. We applied a recently developed behavioral assay, the automated H-maze, to study cognitive functions in Tph2-KI mice. This assay involves the consecutive discovery of three different rules: a delayed alternation task, a non-alternation task, and a delayed reversal task. Possible contribution of locomotion, reward, and sensory perception were also investigated. The expression of loss-of-function mutant Tph2 in mice was associated with impairments in reversal learning and cognitive flexibility, accompanied by perseverative behaviors similar to those observed in human clinical studies. Pharmacological restoration of 5-HT synthesis with 5-hydroxytryptophan or treatment with the 5-HT 2C receptor agonist CP809.101 reduced cognitive deficits in Tph2-KI mice and abolished perseveration. In contrast, treatment with the psychostimulant methylphenidate exacerbated cognitive deficits in mutant mice. Results from this study suggest a contribution of TPH2 in the regulation of cognition. Furthermore, identification of a role for a 5-HT 2 receptor agonist as a cognition-enhancing agent in mutant mice suggests a potential avenue to explore for the personalized treatment of cognitive symptoms in humans with reduced 5-HT synthesis and TPH2 polymorphisms.

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“…The genes encoding these two proteins have been repeatedly, although controversially, linked to various psychiatric disorders in humans (Canli et al, 2008; Gao et al, 2012; Hariri et al, 2005; Hariri & Holmes, 2006; Popova & Kulikov, 2010; Waider et al, 2011; Zhou et al, 2005) and influence anxiety-related personality traits among healthy individuals (Gutknecht et al, 2007; Lesch et al, 1996; Reuter, Kuepper, & Hennig, 2007; Sen, Burmeister, & Ghosh, 2004). …”

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confidence: 99%

“…The TPH2 enzyme is another important regulator of serotonergic function and there exist several polymorphisms in the human TPH2 gene (Gao et al, 2012; Popova & Kulikov, 2010). Unlike 5-HTTLPR, there is no single TPH2 polymorphism that has been particularly well studied or characterized, although several are linked to psychiatric disease, altered amygdala activity and anxiety-related personality traits in a manner similar to 5-HTTLPR (Popova & Kulikov, 2010).…”

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confidence: 99%

Genetic influences on social attention in free-ranging rhesus macaques

Watson

Brent

et al. 2015

Animal Behaviour

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An ethological approach to attention predicts that organisms orient preferentially to valuable sources of information in the environment. For many gregarious species, orienting to other individuals provides valuable social information but competes with food acquisition, water consumption and predator avoidance. Individual variation in vigilance behaviour in humans spans a continuum from inattentive to pathological levels of interest in others. To assess the comparative biology of this behavioural variation, we probed vigilance rates in free-ranging macaques during water drinking, a behaviour incompatible with the gaze and postural demands of vigilance. Males were significantly more vigilant than females. Moreover, vigilance showed a clear genetic component, with an estimated heritability of 12%. Monkeys carrying a relatively infrequent ‘long’ allele of TPH2, a regulatory gene that influences serotonin production in the brain, were significantly less vigilant compared to monkeys that did not carry the allele. These findings resonate with the hypothesis that the serotonin pathway regulates vigilance in primates and by extension provoke the idea that individual variation in vigilance and its underlying biology may be adaptive rather than pathological.

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Targeting tryptophan hydroxylase 2 in affective disorder

Abstract: More comprehensive study of TPH2 genetics is needed to increase the clinical value of the enzyme as a predictor of affective disorder risk and efficacy of antidepressant drugs.

Cited by 31 publications

References 131 publications

Physical Weight Loading Induces Expression of Tryptophan Hydroxylase 2 in the Brain Stem

Physical Weight Loading Induces Expression of Tryptophan Hydroxylase 2 in the Brain Stem

Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation

Genetic influences on social attention in free-ranging rhesus macaques

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