Rev. Neurosci. 2015; aop
Alexander V. Kulikov* and Nina K. Popova
Tryptophan hydroxylase 2 in seasonal affective disorder: underestimated perspectives? Introduction
DOI 10.1515/revneuro-2015-0013 Received March 24, 2015; accepted May 26, 2015
Abstract: Seasonal affective disorder (SAD) is characterized by recurrent depression occurring generally in fall/ winter. Numerous pieces of evidence indicate the association of SAD with decreased brain neurotransmitter serotonin (5-HT) system functioning. Tryptophan hydroxylase 2 (TPH2) is the key and rate-limiting enzyme in 5-HT synthesis in the brain. This paper concentrates on the relationship between TPH2 activity and mood disturbances, the association between human TPH2 gene expression and the risk of affective disorder, application of tryptophan to SAD treatment and the animal models of SAD. The main conclusions of this review are as follows: (i) the brain 5-HT deficiency contributes to the mechanism underlying SAD, (ii) TPH2 is involved in the regulation of some kinds of genetically defined affective disorders and (iii) the activation of 5-HT synthesis with exogenous l-tryptophan alone or in combination with light therapy could be effective in SAD treatment. The synergic effect of these combined treatments will have several advantages compared to light or tryptophan therapy alone. First, it is effective in the treatment of patients resistant to light therapy. Secondly, l-tryptophan treatment prolongs the antidepressant effect of light therapy. Keywords: animal models; light therapy; seasonal affective disorder; serotonin; tryptophan hydroxylase 2; l-tryptophan treatment.
*Corresponding author: Alexander V. Kulikov, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 10 Avenue Lavrentyev, 630090 Novosibirsk, Russia; and Novosibirsk State University, 630090 Novosibirsk, Russia, e-mail: [email protected] Nina K. Popova: Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia; and Novosibirsk State University, 630090 Novosibirsk, Russia
Seasonal affective disorder (SAD) is a complex of depressive-like mood disorders which are characterized by the predictable onset in fall/winter. SAD symptoms are carbohydrate craving, overeating, weight gain, decreased libido, hypersomnia and prominent fatigue (Eagles, 2004; Levitan, 2007). More often SAD affects premenopausal women (Rosenthal et al., 1984). Similar but milder vegetative symptoms often referred to as subsyndromal SAD are observed in many ‘healthy’ adults during fall/winter (Magnusson, 2000). SAD is a considerable social and economic problem due to high risk of disability. Epidemiological studies demonstrate 4–10% of SAD and 11–21% taken together with subsyndromal SAD (Miller, 2005). The frequency of SAD and subsyndromal SAD episodes increases from the south to the north: from 17.6% in the south (Florida) to 48.7% in the north (New Hampshire) individuals feel the worst in winter (Rosen et al., 1990). Numerous pieces of evidence suggest the implication of the decreased brain serotonin (5-HT) system functioning in affective disorders and SAD: (i) the risk of depression is commonly accepted to be associated with deficit of brain 5-HT (Van Praag, 2004); (ii) clinically effective antidepressants increase the 5-HT level in the synaptic cleft; (iii) availability and metabolism of 5-HT in the human brain decrease in fall/winter (Carlsson et al., 1980; Brewerton, 1989); (iv) increased appetite and carbohydrate craving in patients with SAD have been attributed to the decreased central 5-HT functioning (Kräuchi et al., 1990; Arbisi et al., 1996) and (v) the involvement of 5-HT in sleep-wake cycle regulation (Monti, 2011). The idea of the decreased 5-HT brain system functioning as the SAD pathophysiological mechanism stimulates the search of various approaches to elevate the 5-HT level in the brain and to increase the activity of the 5-HT brain system. Although several foods contain 5-HT, it does not cross blood-brain barrier, and in the brain 5-HT is synthesized in 5-HT neurons from essential amino acid l-tryptophan (Figure 1). The key and rate-limiting reaction of 5-HT synthesis is the enzymatic conversion of l-tryptophan to 5-hydroxytryptophan. This reaction is catalyzed by tryptophan hydroxylase (TPH) (Fitzpatrick, 1999, 2003).
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2 A.V. Kulikov and N.K. Popova: TPH 2 and seasonal affective disorder
Figure 1: Synthesis of serotonin and melatonin. In the brain, tryptophan hydroxylase 2 converts l-tryptophan into 5-hydroxytryptophan; then the latter is converted to serotonin by l-aromatic amino acid decarboxylase. In the pineal gland, tryptophan hydroxylase 1 converts l-tryptophan to 5-hydroxytryptophan; then the latter is converted to serotonin by l-aromatic amino acid decarboxylase. Serotonin is acetylated to N-acetylserotonin by aralkylamine N-acetyltransferase. N-acetylserotonin is methylated to serotonin by acetylserotonin O-methyltransferase.
At the same time, the role of TPH in the mechanism of SAD and as a potential target for SAD therapy is questionable. In this review, an association between TPH and SAD as well as future vistas of TPH for potential clinic targeting is discussed. Here we intend to elucidate the following problems: (i) association between TPH activity and mood disorder; (ii) application of l-tryptophan supplementation to SAD treatment; (iii) animal models of SAD.
TPH in 5-HT synthesis in mammals TPH is a member of a small family of four structurally and functionally related tetrahydropterin-dependent l-aromatic amino acid hydroxylases catalyzing the hydroxylation of l-tryptophan, l-tyrosine and l-phenylalanine in the presence of reduced tetrahydrobiopterin (cofactor), O2 and Fe+2 (Fitzpatrick, 1999, 2003). The TPH coding gene in the rat, mouse and human has been sequenced and for a long time
has been thought to be the only TPH gene in the genome (Popova and Kulikov, 2010) till mice genetically deficient in TPH have been bred (Walther et al., 2003). These mice lacked 5-HT in blood, peripheral tissues and the pineal gland. However, it was only a minor 5-HT decrease in the brain structures. These surprising results have led to the discovery of the second TPH gene in the genome of the mouse, rat and human, called TPH2, while the earlier known gene was called TPH1 (Walther and Bader, 2003; Walther et al., 2003). TPH2 is a neuron-specific enzyme expressed in the 5-HT neurons, and its activity is the main factor of 5-HT synthesis in the brain (Walther and Bader, 2003). The discovery of the brain-specific TPH2 showed that there are two 5-HT systems with independent regulation and distinct functions defined by the two TPH genes: TPH1 is expressed in the periphery and the pineal, and TPH2 is expressed in the brain and is responsible for the central effects of 5-HT. TPH1 and TPH2 genes are also distinguished by their localizations on human chromosomes 11 and 12 or mouse chromosomes 7 and 10, respectively (Walther et al., 2003). Discovery of the two independent 5-HT systems sheds new light on the involvement of 5-HT in SAD biology. Although tryptophan is the common substrate for 5-HT synthesis in the pineal gland and the brain, 5-HT is synthesized by different TPH and is linked to quite different mechanisms in these structures (Figure 1). In the pineal gland, 5-HT is the precursor of melatonin and TPH1 does not seem to be the rate-limiting enzyme in melatonin synthesis. Indeed, TPH1 inhibition with p-chlorophenylalanine (pCPA) does not alter melatonin concentration in the pineal gland (Sousa Neto et al., 1995). In contrast, the intrinsic activity of TPH2 is the principal factor in 5-HT synthesis in the brain: pCPA (Mehta et al., 2003; Dailly et al., 2006; Kornum et al., 2006; Kulikov et al., 2012) or TPH2 gene knockout (Gutknecht et al., 2008; Savelieva et al., 2008; Alenina et al., 2009) dramatically reduced 5-HT concentration in the brain. At the same time, the involvement of TPH1 in 5-HT synthesis in the brain is low. TPH1 gene disruption produces a weak effect on the 5-HT level in the mouse brain (Walther et al., 2003; Savelieva et al., 2008). In the adult human brain, TPH1 mRNA is four-fold to six-fold less abundant than that of TPH2 (Zill et al., 2007; Perroud et al., 2010). Although there are some data suggesting TPH1 participating in the brain development (Nakamura and Hasegawa, 2007) or in response to stress (Abumaria et al., 2008), its role in the regulation of behavior is still obscure and needs further investigation (Waider et al., 2011). Taken together, these data allow us to exclude TPH1 and 5-HT of the pineal gland from the list of potential key players in the SAD mechanism.
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A.V. Kulikov and N.K. Popova: TPH 2 and seasonal affective disorder 3
Association between TPH2 and mood disorder The main clinical information on the involvement of TPH2 in the mechanism of affective disorder is obtained from postmortem study and the study of genetic associations between human TPH2 gene polymorphism and depression or suicide risk. There are only a few data on the association between human TPH2 gene expression and the risk of affective disorder. De Luca et al. (2005) found increased TPH2 gene mRNA in the prefrontal cortex of bipolar patients. Some authors observed increased TPH2 protein concentration (Bonkale et al., 2006) and the TPH2 mRNA level in the brain of suicide victims (Underwood et al., 1999, 2004; Boldrini et al., 2005; Bach-Mizrachi et al., 2006, 2008). However, other authors did not find any association between TPH2 gene expression, suicide (De Luca et al., 2006), affective disorders and schizophrenia (Shamir et al., 2005). There is no information on TPH2 activity or expression in the brain of patients with SAD or on the effect of photoperiod on the enzyme activity in the human brain. Since getting the direct assay of TPH2 expression and activity in the human brain is complicated due to ethic and technique problems, the study of the association between the mutations of the human TPH2 gene and the risk of psychopathology is the commonly accepted approach. Five years ago we referred 678 single nucleotide polymorphisms (SNPs) in human TPH2 gene (Popova and Kulikov, 2010). Currently, 2794 SNPs in human TPH2 gene were registered (http://www.ncbi.nlm.nh.gov). Among them, three common mutations -703G > T (rs4570625) (Lin et al., 2007), -437T > A (rs11178337) (Lin et al., 2007) and 90A > G (rs11178998) (Scheuch et al., 2007) in the TPH2 gene promoter as well as nine rare mutations in the regulatory, catalytic and tetrameri zation domains (Patel et al., 2007; Popova and Kulikov, 2010) were considered as associated with mental disorders. Prevalent haplotype of three common mutations in Caucasians, GTA, provides the highest TPH2 expression in cell cultures, while other haplotypes, TTA (Chen et al., 2008), TAG and GAA (Scheuch et al., 2007), decrease the gene expression. However, De Luca et al. (2005, 2006) did not show any association between the -473T > A polymorphism and the TPH2 mRNA level in the human brain. So, the regulation of TPH2 gene expression in vitro seems to be different from that in the human brain, and more pieces of experimental evidence are needed to confirm the functional meanings of these SNPs. In general, the data on the association between these common polymorphisms in the TPH2 gene promoter and affective disorders obtained in
various ethnic groups are rather contradictory (Mössner et al., 2006; Van Den Bogaert et al., 2006; Lin et al., 2007; Cichon et al., 2008; Kim et al., 2009) suggesting ethnic background in the effects of these mutations. Among nine missense mutations of human TPH2 gene, three mutations in the regulatory domain and one in the tetramerization domain did not affect enzyme activity, while three mutations in the catalytic (P206S, R303W, A328V) and one in the tetramerization (R441H) domains dramatically reduced in vitro TPH2 activity (Zhang et al., 2005; McKinney et al., 2009). All these mutations are rare and found in a small number of subjects: their frequencies in different ethnic populations do not exceed 1%. Four missense mutations in the coding parts of human TPH2 gene (S41Y, P206S, R303W, R441H) are associated with mental disorders. The S41Y mutation was associated with bipolar disorder in Han Chinese, although, surprisingly, the rare 41Y allele which decreased TPH2 activity in vitro was more frequent in the controls than in the affected patients (7 out of 101 controls and 1 out of 104 patients) (Lin et al., 2007). The rare P206S mutation was transmitted together with predisposition to bipolar disorder in the German and Russian families (Cichon et al., 2008). This mutation was detected in 3 out of 1300 controls and in 6 out of 883 depressive patients. The R303W mutation was detected in a woman and her daughter with the attention deficit hyperactivity disorder (McKinney et al., 2009). The R441H mutation was found in 9 out of 87 unipolar depression patients and only in 3 out of 219 controls (Zhang et al., 2005). This mutation is extremely rare and other authors failed to detect it (Garriock et al., 2005; Glatt et al., 2005; Zhou et al., 2005; Delorme et al., 2006; H enningsson et al., 2007). The rarity of these mutations suggests the influence of natural selection against them supporting the idea of their negative effect on behavior. Recently, an involvement of common G6493A polymorphism (SNP rs1389493) located in the fifth intron of human TPH2 gene in the regulation of the enzyme activity was shown (Zhang et al., 2011). The decreased efficiency of normal RNA splicing with increased alternative splicing producing truncated TPH2 mRNA in 6394A allele carriers was found. The truncated form of TPH2 protein lacks the normal enzyme activity. The frequency of the 6493A allele in human population is about 18–20% (Zhang et al., 2011). At present, no association between the G6493A polymorphism and the risk of depression and suicide has been observed. However, a possible involvement of this polymorphism in genetically defined predisposition to SAD cannot be ignored. No association between TPH1 gene polymorphisms and the risk of SAD was found (Han et al., 1999; Johansson
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4 A.V. Kulikov and N.K. Popova: TPH 2 and seasonal affective disorder et al., 2001). There are no data on any association between human TPH2 gene polymorphism and SAD.
Association between TPH2 and depressive-like behavior in mouse models Immobility time in the forced swim (FST) or in the tail suspension (TST) tests is a commonly used index of depressive-like behavior and antidepressant activity, since it is reduced with all clinically effective antidepressants (Willner, 1990; Willner and Mitchell, 2002; Cryan and Mombereau, 2004; Yacoubi and Vaugeois, 2007). The main pieces of experimental evidence on the association between TPH2 and depressive-like immobility in these tests came from the data on the effect of genetic and pharmacological alterations in the TPH2 activity (Table 1). TPH2 gene deficiency reduces the 5-HT level in the brain down to 4% and produces growth retardation, maternal neglect of the pups, affected body temperature control, decreased blood pressure, heart and breath rates, increased marble burying and sleeping (Savelieva et al., 2008; Alenina et al., 2009). The latter effect is especially interesting as hypersomnia frequently accompanies SAD (Levitan, 2007). At the same time, the effects of TPH2 gene knockout on locomotion, exploration, anxiety or depressive-related behavior are rather modest. No alteration in behavior in the open field test, acoustic startle response and fear conditioning in TPH2 deficient mice was observed (Savelieva et al., 2008). Although the effect of TPH2 gene deficiency on the FST is controversial (Savelieva et al., 2008; Osipova et al., 2009; Mosienko et al., 2012), decreased immobility time in the FST shown
by Savelieva et al. (2008) and Osipova et al. (2009) agrees with the effect of the TPH inhibitor pCPA (Borsini and Meli, 1988; Borsini, 1995). An interesting animal model is the functional singlenucleotide C1473G polymorphism in mouse TPH2 gene resulting in the replacement of Pro447 by Arg (P447R) in the enzyme molecule (Zhang et al., 2004). The two-fold decrease of TPH2 activity in the brain of mice carrying mutant G allele (BALB/c, DBA2, A/He, CC57BR) was found (Kulikov et al., 2005; Osipova et al., 2010). Allele G was transferred from the CC57BR strain to the C57BL/6 genome, and two congenic lines B6-1473G and B6-1473C, respectively, with low and high TPH2 activity in the brain were bred (Osipova et al., 2009). Decreased immobility time in the FST in B6-1473G congenic mice with low TPH2 activity was found (Figure 2) (Osipova et al., 2009). However, other authors who used the DBA2 mouse as the donor of G allele did not find any effect of G allele on the FST (Tenner et al., 2008). Although G allele dramatically reduces TPH2 activity, it does not seem to affect the 5-HT level or metabolism in the mouse brain (Siesser et al., 2010). At the same time, mice with R439H knock-in of TPH2 gene show the decreased 5-HT level in the brain and increased immobility in the FST (Beaulieu et al., 2008) similar to TPH2 gene-deficient mice described by Mosienko et al. (2012). These discrepancies in the effects of TPH2 deficiency on the depressive-like immobility shown on different mouse strains suggest considerable effect of the genetic background on the association between TPH2 gene and the behavior in the FST. The FST was firstly developed and proved as an effective test for antidepressant activity (Willner, 1990), while there is no correct interpretation of the test application to the interstrain comparison. Therefore, a certain caution is needed to interpret the effect of genetically defined TPH2 deficiency on immobility in the FST as evidence of a relationship between TPH2 deficiency and risk of depression.
Table 1: Association between TPH2 activity and depressive-like behavior in mouse models. Behavior
Mouse depressive-like immobility in the FST Resistance to citalopram in the FST in the TST
Model
TPH2 gene knockout pCPA treatment P447R polymorphism R439H knock-in P447R polymorphism
Effect
↓ ↑ ↓ ↓ (447R) NE ↑ (439H) ↑ (447R) NE
↑, increase; ↓, decrease; NE, no effect; FST, forced swim test; TST, tail suspension test.
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References Savelieva et al., 2008 Mosienko et al., 2012 Borsini and Meli, 1988; Borsini, 1995 Osipova et al., 2009 Tenner et al., 2008; Siesser et al., 2010 Beaulieu et al., 2008 Cervo et al., 2005; Guzzetti et al., 2008; Kulikov et al., 2011 Siesser et al., 2010
A.V. Kulikov and N.K. Popova: TPH 2 and seasonal affective disorder 5
TPh2 activity in midbrain
60
60 50 40 30 20 10 0
Forced swim
50 Immobility time (s)
TPH2 activity (pmol/mg/min)
70
B6-1473C
B6-1473G
40 30 20 10 0
B6-1473C
B6-1473G
Figure 2: TPH2 activity and immobility in the FST in mice of B6-1473C and B6-1473G congenic strains (from Osipova et al., 2009). *p A, 90A > G and rs1386493 as possible predictors of SAD risk. This may be the target for future clinical investigations with high clinical and fundamental impact. Discovery of alternative splicing and RNA editing of TPH2 transcripts in the human brain (Grohmann et al., 2010) provides new vistas for controlling TPH2 expression and activity. The most promising finding is the recent demonstration of the effect of G6493A common polymorphism on mRNA TPH2 splicing in human. Since the frequency of decreasing TPH2 activity 6493A allele in human populations is rather high (18–20%) (Zhang et al., 2011), this polymorphism should be considered when choosing a therapy of SAD. In perspective, development of new drugs selectively activating TPH2 expression or/and activity could markedly increase the clinical value of the enzyme as a target for SAD therapy (Matthes et al., 2010).
The exact relationship between the shortage of the daylight, TPH2 activity, deficient 5-HT neurotransmission and depression risk remains to be elucidated. The finding that the short-day condition induces depressivelike alterations in behavior and 5-HT metabolism in the brain of C57BL/6 mice (Otsuka et al., 2014) provides a new possibility for the experimental study of the interaction between photoperiod, TPH2 and behavior. Currently there are several TPH2-deficient C57BL/6-derived mouse lines, such as TPH2 knockout mice (Savelieva et al., 2008; Alenina et al., 2009), R439H knock-in mice (Jacobsen et al., 2012) and mice with G allele of functional C1473G polymorphism in TPH2 gene (Osipova et al., 2009; Siesser et al., 2010). These mouse lines are suitable experimental tools to clarify the role of TPH2 deficiency in the mechanism of vulnerability to short-day condition. We hope that further studies of the association between the common polymorphisms in the human TPH2 gene and SAD as well as the effect of the short-day condition on mice with genetically defined differences in TPH2 activity will increase the clinical value of the enzyme as a predictor of SAD risk and efficacy of SAD therapy. Acknowledgments: This study was supported by Russian Scientific Foundation (grant no. 14-25-00038).
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Alexander V. Kulikov* and Nina K. Popova
Tryptophan hydroxylase 2 in seasonal affective disorder: underestimated perspectives? Introduction
DOI 10.1515/revneuro-2015-0013 Received March 24, 2015; accepted May 26, 2015
Abstract: Seasonal affective disorder (SAD) is characterized by recurrent depression occurring generally in fall/ winter. Numerous pieces of evidence indicate the association of SAD with decreased brain neurotransmitter serotonin (5-HT) system functioning. Tryptophan hydroxylase 2 (TPH2) is the key and rate-limiting enzyme in 5-HT synthesis in the brain. This paper concentrates on the relationship between TPH2 activity and mood disturbances, the association between human TPH2 gene expression and the risk of affective disorder, application of tryptophan to SAD treatment and the animal models of SAD. The main conclusions of this review are as follows: (i) the brain 5-HT deficiency contributes to the mechanism underlying SAD, (ii) TPH2 is involved in the regulation of some kinds of genetically defined affective disorders and (iii) the activation of 5-HT synthesis with exogenous l-tryptophan alone or in combination with light therapy could be effective in SAD treatment. The synergic effect of these combined treatments will have several advantages compared to light or tryptophan therapy alone. First, it is effective in the treatment of patients resistant to light therapy. Secondly, l-tryptophan treatment prolongs the antidepressant effect of light therapy. Keywords: animal models; light therapy; seasonal affective disorder; serotonin; tryptophan hydroxylase 2; l-tryptophan treatment.
*Corresponding author: Alexander V. Kulikov, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 10 Avenue Lavrentyev, 630090 Novosibirsk, Russia; and Novosibirsk State University, 630090 Novosibirsk, Russia, e-mail: [email protected] Nina K. Popova: Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia; and Novosibirsk State University, 630090 Novosibirsk, Russia
Seasonal affective disorder (SAD) is a complex of depressive-like mood disorders which are characterized by the predictable onset in fall/winter. SAD symptoms are carbohydrate craving, overeating, weight gain, decreased libido, hypersomnia and prominent fatigue (Eagles, 2004; Levitan, 2007). More often SAD affects premenopausal women (Rosenthal et al., 1984). Similar but milder vegetative symptoms often referred to as subsyndromal SAD are observed in many ‘healthy’ adults during fall/winter (Magnusson, 2000). SAD is a considerable social and economic problem due to high risk of disability. Epidemiological studies demonstrate 4–10% of SAD and 11–21% taken together with subsyndromal SAD (Miller, 2005). The frequency of SAD and subsyndromal SAD episodes increases from the south to the north: from 17.6% in the south (Florida) to 48.7% in the north (New Hampshire) individuals feel the worst in winter (Rosen et al., 1990). Numerous pieces of evidence suggest the implication of the decreased brain serotonin (5-HT) system functioning in affective disorders and SAD: (i) the risk of depression is commonly accepted to be associated with deficit of brain 5-HT (Van Praag, 2004); (ii) clinically effective antidepressants increase the 5-HT level in the synaptic cleft; (iii) availability and metabolism of 5-HT in the human brain decrease in fall/winter (Carlsson et al., 1980; Brewerton, 1989); (iv) increased appetite and carbohydrate craving in patients with SAD have been attributed to the decreased central 5-HT functioning (Kräuchi et al., 1990; Arbisi et al., 1996) and (v) the involvement of 5-HT in sleep-wake cycle regulation (Monti, 2011). The idea of the decreased 5-HT brain system functioning as the SAD pathophysiological mechanism stimulates the search of various approaches to elevate the 5-HT level in the brain and to increase the activity of the 5-HT brain system. Although several foods contain 5-HT, it does not cross blood-brain barrier, and in the brain 5-HT is synthesized in 5-HT neurons from essential amino acid l-tryptophan (Figure 1). The key and rate-limiting reaction of 5-HT synthesis is the enzymatic conversion of l-tryptophan to 5-hydroxytryptophan. This reaction is catalyzed by tryptophan hydroxylase (TPH) (Fitzpatrick, 1999, 2003).
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2 A.V. Kulikov and N.K. Popova: TPH 2 and seasonal affective disorder
Figure 1: Synthesis of serotonin and melatonin. In the brain, tryptophan hydroxylase 2 converts l-tryptophan into 5-hydroxytryptophan; then the latter is converted to serotonin by l-aromatic amino acid decarboxylase. In the pineal gland, tryptophan hydroxylase 1 converts l-tryptophan to 5-hydroxytryptophan; then the latter is converted to serotonin by l-aromatic amino acid decarboxylase. Serotonin is acetylated to N-acetylserotonin by aralkylamine N-acetyltransferase. N-acetylserotonin is methylated to serotonin by acetylserotonin O-methyltransferase.
At the same time, the role of TPH in the mechanism of SAD and as a potential target for SAD therapy is questionable. In this review, an association between TPH and SAD as well as future vistas of TPH for potential clinic targeting is discussed. Here we intend to elucidate the following problems: (i) association between TPH activity and mood disorder; (ii) application of l-tryptophan supplementation to SAD treatment; (iii) animal models of SAD.
TPH in 5-HT synthesis in mammals TPH is a member of a small family of four structurally and functionally related tetrahydropterin-dependent l-aromatic amino acid hydroxylases catalyzing the hydroxylation of l-tryptophan, l-tyrosine and l-phenylalanine in the presence of reduced tetrahydrobiopterin (cofactor), O2 and Fe+2 (Fitzpatrick, 1999, 2003). The TPH coding gene in the rat, mouse and human has been sequenced and for a long time
has been thought to be the only TPH gene in the genome (Popova and Kulikov, 2010) till mice genetically deficient in TPH have been bred (Walther et al., 2003). These mice lacked 5-HT in blood, peripheral tissues and the pineal gland. However, it was only a minor 5-HT decrease in the brain structures. These surprising results have led to the discovery of the second TPH gene in the genome of the mouse, rat and human, called TPH2, while the earlier known gene was called TPH1 (Walther and Bader, 2003; Walther et al., 2003). TPH2 is a neuron-specific enzyme expressed in the 5-HT neurons, and its activity is the main factor of 5-HT synthesis in the brain (Walther and Bader, 2003). The discovery of the brain-specific TPH2 showed that there are two 5-HT systems with independent regulation and distinct functions defined by the two TPH genes: TPH1 is expressed in the periphery and the pineal, and TPH2 is expressed in the brain and is responsible for the central effects of 5-HT. TPH1 and TPH2 genes are also distinguished by their localizations on human chromosomes 11 and 12 or mouse chromosomes 7 and 10, respectively (Walther et al., 2003). Discovery of the two independent 5-HT systems sheds new light on the involvement of 5-HT in SAD biology. Although tryptophan is the common substrate for 5-HT synthesis in the pineal gland and the brain, 5-HT is synthesized by different TPH and is linked to quite different mechanisms in these structures (Figure 1). In the pineal gland, 5-HT is the precursor of melatonin and TPH1 does not seem to be the rate-limiting enzyme in melatonin synthesis. Indeed, TPH1 inhibition with p-chlorophenylalanine (pCPA) does not alter melatonin concentration in the pineal gland (Sousa Neto et al., 1995). In contrast, the intrinsic activity of TPH2 is the principal factor in 5-HT synthesis in the brain: pCPA (Mehta et al., 2003; Dailly et al., 2006; Kornum et al., 2006; Kulikov et al., 2012) or TPH2 gene knockout (Gutknecht et al., 2008; Savelieva et al., 2008; Alenina et al., 2009) dramatically reduced 5-HT concentration in the brain. At the same time, the involvement of TPH1 in 5-HT synthesis in the brain is low. TPH1 gene disruption produces a weak effect on the 5-HT level in the mouse brain (Walther et al., 2003; Savelieva et al., 2008). In the adult human brain, TPH1 mRNA is four-fold to six-fold less abundant than that of TPH2 (Zill et al., 2007; Perroud et al., 2010). Although there are some data suggesting TPH1 participating in the brain development (Nakamura and Hasegawa, 2007) or in response to stress (Abumaria et al., 2008), its role in the regulation of behavior is still obscure and needs further investigation (Waider et al., 2011). Taken together, these data allow us to exclude TPH1 and 5-HT of the pineal gland from the list of potential key players in the SAD mechanism.
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A.V. Kulikov and N.K. Popova: TPH 2 and seasonal affective disorder 3
Association between TPH2 and mood disorder The main clinical information on the involvement of TPH2 in the mechanism of affective disorder is obtained from postmortem study and the study of genetic associations between human TPH2 gene polymorphism and depression or suicide risk. There are only a few data on the association between human TPH2 gene expression and the risk of affective disorder. De Luca et al. (2005) found increased TPH2 gene mRNA in the prefrontal cortex of bipolar patients. Some authors observed increased TPH2 protein concentration (Bonkale et al., 2006) and the TPH2 mRNA level in the brain of suicide victims (Underwood et al., 1999, 2004; Boldrini et al., 2005; Bach-Mizrachi et al., 2006, 2008). However, other authors did not find any association between TPH2 gene expression, suicide (De Luca et al., 2006), affective disorders and schizophrenia (Shamir et al., 2005). There is no information on TPH2 activity or expression in the brain of patients with SAD or on the effect of photoperiod on the enzyme activity in the human brain. Since getting the direct assay of TPH2 expression and activity in the human brain is complicated due to ethic and technique problems, the study of the association between the mutations of the human TPH2 gene and the risk of psychopathology is the commonly accepted approach. Five years ago we referred 678 single nucleotide polymorphisms (SNPs) in human TPH2 gene (Popova and Kulikov, 2010). Currently, 2794 SNPs in human TPH2 gene were registered (http://www.ncbi.nlm.nh.gov). Among them, three common mutations -703G > T (rs4570625) (Lin et al., 2007), -437T > A (rs11178337) (Lin et al., 2007) and 90A > G (rs11178998) (Scheuch et al., 2007) in the TPH2 gene promoter as well as nine rare mutations in the regulatory, catalytic and tetrameri zation domains (Patel et al., 2007; Popova and Kulikov, 2010) were considered as associated with mental disorders. Prevalent haplotype of three common mutations in Caucasians, GTA, provides the highest TPH2 expression in cell cultures, while other haplotypes, TTA (Chen et al., 2008), TAG and GAA (Scheuch et al., 2007), decrease the gene expression. However, De Luca et al. (2005, 2006) did not show any association between the -473T > A polymorphism and the TPH2 mRNA level in the human brain. So, the regulation of TPH2 gene expression in vitro seems to be different from that in the human brain, and more pieces of experimental evidence are needed to confirm the functional meanings of these SNPs. In general, the data on the association between these common polymorphisms in the TPH2 gene promoter and affective disorders obtained in
various ethnic groups are rather contradictory (Mössner et al., 2006; Van Den Bogaert et al., 2006; Lin et al., 2007; Cichon et al., 2008; Kim et al., 2009) suggesting ethnic background in the effects of these mutations. Among nine missense mutations of human TPH2 gene, three mutations in the regulatory domain and one in the tetramerization domain did not affect enzyme activity, while three mutations in the catalytic (P206S, R303W, A328V) and one in the tetramerization (R441H) domains dramatically reduced in vitro TPH2 activity (Zhang et al., 2005; McKinney et al., 2009). All these mutations are rare and found in a small number of subjects: their frequencies in different ethnic populations do not exceed 1%. Four missense mutations in the coding parts of human TPH2 gene (S41Y, P206S, R303W, R441H) are associated with mental disorders. The S41Y mutation was associated with bipolar disorder in Han Chinese, although, surprisingly, the rare 41Y allele which decreased TPH2 activity in vitro was more frequent in the controls than in the affected patients (7 out of 101 controls and 1 out of 104 patients) (Lin et al., 2007). The rare P206S mutation was transmitted together with predisposition to bipolar disorder in the German and Russian families (Cichon et al., 2008). This mutation was detected in 3 out of 1300 controls and in 6 out of 883 depressive patients. The R303W mutation was detected in a woman and her daughter with the attention deficit hyperactivity disorder (McKinney et al., 2009). The R441H mutation was found in 9 out of 87 unipolar depression patients and only in 3 out of 219 controls (Zhang et al., 2005). This mutation is extremely rare and other authors failed to detect it (Garriock et al., 2005; Glatt et al., 2005; Zhou et al., 2005; Delorme et al., 2006; H enningsson et al., 2007). The rarity of these mutations suggests the influence of natural selection against them supporting the idea of their negative effect on behavior. Recently, an involvement of common G6493A polymorphism (SNP rs1389493) located in the fifth intron of human TPH2 gene in the regulation of the enzyme activity was shown (Zhang et al., 2011). The decreased efficiency of normal RNA splicing with increased alternative splicing producing truncated TPH2 mRNA in 6394A allele carriers was found. The truncated form of TPH2 protein lacks the normal enzyme activity. The frequency of the 6493A allele in human population is about 18–20% (Zhang et al., 2011). At present, no association between the G6493A polymorphism and the risk of depression and suicide has been observed. However, a possible involvement of this polymorphism in genetically defined predisposition to SAD cannot be ignored. No association between TPH1 gene polymorphisms and the risk of SAD was found (Han et al., 1999; Johansson
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4 A.V. Kulikov and N.K. Popova: TPH 2 and seasonal affective disorder et al., 2001). There are no data on any association between human TPH2 gene polymorphism and SAD.
Association between TPH2 and depressive-like behavior in mouse models Immobility time in the forced swim (FST) or in the tail suspension (TST) tests is a commonly used index of depressive-like behavior and antidepressant activity, since it is reduced with all clinically effective antidepressants (Willner, 1990; Willner and Mitchell, 2002; Cryan and Mombereau, 2004; Yacoubi and Vaugeois, 2007). The main pieces of experimental evidence on the association between TPH2 and depressive-like immobility in these tests came from the data on the effect of genetic and pharmacological alterations in the TPH2 activity (Table 1). TPH2 gene deficiency reduces the 5-HT level in the brain down to 4% and produces growth retardation, maternal neglect of the pups, affected body temperature control, decreased blood pressure, heart and breath rates, increased marble burying and sleeping (Savelieva et al., 2008; Alenina et al., 2009). The latter effect is especially interesting as hypersomnia frequently accompanies SAD (Levitan, 2007). At the same time, the effects of TPH2 gene knockout on locomotion, exploration, anxiety or depressive-related behavior are rather modest. No alteration in behavior in the open field test, acoustic startle response and fear conditioning in TPH2 deficient mice was observed (Savelieva et al., 2008). Although the effect of TPH2 gene deficiency on the FST is controversial (Savelieva et al., 2008; Osipova et al., 2009; Mosienko et al., 2012), decreased immobility time in the FST shown
by Savelieva et al. (2008) and Osipova et al. (2009) agrees with the effect of the TPH inhibitor pCPA (Borsini and Meli, 1988; Borsini, 1995). An interesting animal model is the functional singlenucleotide C1473G polymorphism in mouse TPH2 gene resulting in the replacement of Pro447 by Arg (P447R) in the enzyme molecule (Zhang et al., 2004). The two-fold decrease of TPH2 activity in the brain of mice carrying mutant G allele (BALB/c, DBA2, A/He, CC57BR) was found (Kulikov et al., 2005; Osipova et al., 2010). Allele G was transferred from the CC57BR strain to the C57BL/6 genome, and two congenic lines B6-1473G and B6-1473C, respectively, with low and high TPH2 activity in the brain were bred (Osipova et al., 2009). Decreased immobility time in the FST in B6-1473G congenic mice with low TPH2 activity was found (Figure 2) (Osipova et al., 2009). However, other authors who used the DBA2 mouse as the donor of G allele did not find any effect of G allele on the FST (Tenner et al., 2008). Although G allele dramatically reduces TPH2 activity, it does not seem to affect the 5-HT level or metabolism in the mouse brain (Siesser et al., 2010). At the same time, mice with R439H knock-in of TPH2 gene show the decreased 5-HT level in the brain and increased immobility in the FST (Beaulieu et al., 2008) similar to TPH2 gene-deficient mice described by Mosienko et al. (2012). These discrepancies in the effects of TPH2 deficiency on the depressive-like immobility shown on different mouse strains suggest considerable effect of the genetic background on the association between TPH2 gene and the behavior in the FST. The FST was firstly developed and proved as an effective test for antidepressant activity (Willner, 1990), while there is no correct interpretation of the test application to the interstrain comparison. Therefore, a certain caution is needed to interpret the effect of genetically defined TPH2 deficiency on immobility in the FST as evidence of a relationship between TPH2 deficiency and risk of depression.
Table 1: Association between TPH2 activity and depressive-like behavior in mouse models. Behavior
Mouse depressive-like immobility in the FST Resistance to citalopram in the FST in the TST
Model
TPH2 gene knockout pCPA treatment P447R polymorphism R439H knock-in P447R polymorphism
Effect
↓ ↑ ↓ ↓ (447R) NE ↑ (439H) ↑ (447R) NE
↑, increase; ↓, decrease; NE, no effect; FST, forced swim test; TST, tail suspension test.
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References Savelieva et al., 2008 Mosienko et al., 2012 Borsini and Meli, 1988; Borsini, 1995 Osipova et al., 2009 Tenner et al., 2008; Siesser et al., 2010 Beaulieu et al., 2008 Cervo et al., 2005; Guzzetti et al., 2008; Kulikov et al., 2011 Siesser et al., 2010
A.V. Kulikov and N.K. Popova: TPH 2 and seasonal affective disorder 5
TPh2 activity in midbrain
60
60 50 40 30 20 10 0
Forced swim
50 Immobility time (s)
TPH2 activity (pmol/mg/min)
70
B6-1473C
B6-1473G
40 30 20 10 0
B6-1473C
B6-1473G
Figure 2: TPH2 activity and immobility in the FST in mice of B6-1473C and B6-1473G congenic strains (from Osipova et al., 2009). *p A, 90A > G and rs1386493 as possible predictors of SAD risk. This may be the target for future clinical investigations with high clinical and fundamental impact. Discovery of alternative splicing and RNA editing of TPH2 transcripts in the human brain (Grohmann et al., 2010) provides new vistas for controlling TPH2 expression and activity. The most promising finding is the recent demonstration of the effect of G6493A common polymorphism on mRNA TPH2 splicing in human. Since the frequency of decreasing TPH2 activity 6493A allele in human populations is rather high (18–20%) (Zhang et al., 2011), this polymorphism should be considered when choosing a therapy of SAD. In perspective, development of new drugs selectively activating TPH2 expression or/and activity could markedly increase the clinical value of the enzyme as a target for SAD therapy (Matthes et al., 2010).
The exact relationship between the shortage of the daylight, TPH2 activity, deficient 5-HT neurotransmission and depression risk remains to be elucidated. The finding that the short-day condition induces depressivelike alterations in behavior and 5-HT metabolism in the brain of C57BL/6 mice (Otsuka et al., 2014) provides a new possibility for the experimental study of the interaction between photoperiod, TPH2 and behavior. Currently there are several TPH2-deficient C57BL/6-derived mouse lines, such as TPH2 knockout mice (Savelieva et al., 2008; Alenina et al., 2009), R439H knock-in mice (Jacobsen et al., 2012) and mice with G allele of functional C1473G polymorphism in TPH2 gene (Osipova et al., 2009; Siesser et al., 2010). These mouse lines are suitable experimental tools to clarify the role of TPH2 deficiency in the mechanism of vulnerability to short-day condition. We hope that further studies of the association between the common polymorphisms in the human TPH2 gene and SAD as well as the effect of the short-day condition on mice with genetically defined differences in TPH2 activity will increase the clinical value of the enzyme as a predictor of SAD risk and efficacy of SAD therapy. Acknowledgments: This study was supported by Russian Scientific Foundation (grant no. 14-25-00038).
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