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Signal transducer and activator of transcription 6 (STAT6) and attention-deficit hyperactivity disorder: A speculative hypothesis
Medical Hypotheses (2006) 67, 1341–1343
http://intl.elsevierhealth.com/journals/mehy
Signal transducer and activator of transcription 6 (STAT6) and attention-deficit hyperactivity disorder: A speculative hypothesis Shih-Jen Tsai
*
Department of Psychiatry, Taipei Veterans General Hospital, Taiwan Division of Psychiatry, School of Medicine, National Yang-Ming University, Taiwan Received 9 May 2006; accepted 11 May 2006
Summary Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by hyperactivity, impulsiveness and inattention that begins in childhood. The underlying pathogenesis of this disorder is still unknown, although pharmacological, genetic and neuroimaging studies suggest that dopamine transportation may be implicated in the pathogenesis of ADHD. Signal transducer and activator of transcription 6 (STAT6), similar to other members of the signal transducer and activator of transcription family of proteins, is an important molecule in the induction and regulation of the immune response. Animal studies have demonstrated that STAT6 is highly expressed in the CNS, especially in the developing brain. Recent studies have demonstrated that STAT6-deficient mice exhibit increased locomotor activity and decreased levels of dopamine transporter expression in the striatum, when compared with the wild-type. From these findings, and evidence from other studies, it can be proposed that STAT6 may be implicated in the pathogenesis of ADHD. Several proposals to test this hypothesis are suggested; attempts to prove the STAT6–ADHD hypothesis may provide a new direction that elucidates the pathogenesis of and a treatment for ADHD. c 2006 Elsevier Ltd. All rights reserved.
Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder with onset at preschool age. The core symptoms include hyperactivity, impulsive, and inattention and it is associated with substantial life impairments and sometimes persists into adulthood. Although the biological basis of ADHD is still unknown, recent studies have suggested that this disorder is highly * Department of Psychiatry, Taipei Veterans General Hospital, No. 201 Shih-Pai Road, Section 2, 11217 Taipei, Taiwan. Tel.: +886 2 28757027x276; fax: +886 2 28725643. E-mail address: [email protected].
heritable and may be associated with neurobiological deficits in the prefrontal cortex and related subcortical systems [1]. Moreover, the effectiveness of stimulants, along with animal models of hyperactivity, point to catecholamine (dopamine and norepinephrine) circuit dys-regulation as at least one source of ADHD brain dysfunction [2,3]. Although the ‘‘catecholamine hypothesis’’ has been the major theory for the pathogenesis of ADHD, it cannot successfully account for the underlying pathophysiology. In this way, hypotheses about the cause of ADHD have evolved from simple one-cause theories to theories that describe
0306-9877/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2006.05.019
1342 a complex and multifactorial disorder [2]. For example, recent family-based genetic studies have demonstrated that brain-derived neurotrophic factor (BDNF) genetic variation is associated with ADHD susceptibility [4–6]. This supports the hypothesis that BDNF is involved in the pathogenesis of ADHD [7]. Although many hypotheses exist to describe the aetiology of ADHD, no one hypothesis satisfactorily accounts for all cases. Here, I propose that signal transducer and activator of transcription 6 (STAT6) may be implicated in the pathogenesis of ADHD. STAT6, similar to other members of the signal transducer and activator of transcription (STAT) family of proteins, provides a direct link between the cytokine receptors and cytokine-induced gene transcription. STAT6 specifically mediates signals that emanate from interleukin 4 (IL-4) receptors [8]. As an important molecule in the induction and regulation of the immune response, STAT6 has been implicated in the pathogenesis of allergic and inflammatory diseases [9,10]. In animal studies, De-Fraja and colleagues demonstrated that in the adult rat brain, STAT6 is expressed in the cortex, basal forebrain and hippocampus, while in the developing rat brain, high levels of STAT6 were found in striatum, cortex and hippocampus [11,12]. This suggests that STAT6 may play an important role in brain function and brain development [13]. This notion is further supported by a recent study by Yukawa and colleagues, who used a battery of murine behavioural analyses of STAT6-deficient mice, and suggested that STAT6-deficient mice may provide crucial information to the underlying pathophysiology of mental illness [14,15]. These findings from behavioural testing in STAT6-deficient mice, as well as evidence from other studies suggest that STAT6 may play a role in the pathogenesis of ADHD. Some evidences to support this hypothesis are suggested below. Firstly, in an animal study of genetically-modified STAT6-deficient mice, increased locomotor activity was observed compared to controls [14]. This mimics the fundamental behavioural characteristics of ADHD (face validity) [16]. Secondly, in the STAT6-deficient mouse, a reduced level of dopamine transporter (DAT) expression in the striatum was found when compared with the wild-type [14]. Dopamine transporters are the site of primary action of the stimulants that are known to be effective in the treatment of ADHD [17]. A recent positron emission tomography (PET) study demonstrated lower binding to DAT in the midbrain of adolescents with ADHD [18]. Furthermore, genetic studies had suggested association between ADHD and the 10-repeat allele of a
Tsai 40 base pair variable number of tandem repeats polymorphism of DAT gene [2]. Thirdly, ADHD is a common neurodevelopmental disorder that begins in childhood [19]. Genes, such as STAT6, are highly expressed in developing brains and may be involved in brain development [11–13], and are thus possibly important etiological factors in ADHD. Finally, immune system dys-regulation has been implicated in the pathogenesis of ADHD [20,21]. In a genetic association study, a preferential transmission of interleukin-1 receptor antagonist alleles in ADHD patients has been demonstrated [22]. This finding points to a role for brain cytokine activity in the pathogenesis of ADHD. STAT6, which provides a direct link between the cytokine receptors and cytokine-induced gene transcription, may bring about ADHD pathogenesis through immune regulation. The above evidence suggests that STAT6 plays a role in the pathogenesis of ADHD. In order to test this hypothesis, several proposals are presented in this paper. Firstly, the IL4-induced STAT6 signaling pathway is active in a variety of cell types and there are large quantitative differences in DNAbinding activities of IL4-induced STAT6, which is useful for phenotyping activated STAT6 in normal and diseased statuses. The recently-developed semi-quantitative methodology for testing STAT6 activities [23] could be used in lymphoblastoid cell lines from ADHD subjects to test for abnormalities in STAT6 activities. Secondly, molecular genetic studies show ADHD to be a common, multifactorial disorder with significant genetic contributions [2]. Common genetic polymorphisms, which are related to STAT6 expression, such as G2964A polymorphism [24] and dinucleotide (GT) repeat in exon 1 [25] of the STAT6 gene may be related to the risk, the clinical manifestations or the endophenotypes (e.g. central dopamine transporter density) of ADHD. Thirdly, most studies support stimulants as the best available pharmacotherapy for the treatment of children with ADHD. The effects of stimulants such as methylphenidate on the locomotor activity of STAT6-deficient mice may help to confirm a theoretical rationale for STAT6 in ADHD. Attempts to prove the STAT6–ADHD hypothesis may lead investigators in a new direction of study of the pathogenesis of ADHD and the development of an effective intervention for this disorder.
References [1] Spencer TJ, Biederman J, Wilens TE, Faraone SV. Overview and neurobiology of attention-deficit/hyperactivity disorder. J Clin Psychiatr 2002;63(suppl. 12):3–9.
Signal transducer and activator of transcription 6 (STAT6) and attention-deficit hyperactivity disorder 1343 [2] Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet 2005;366:237–48. [3] Pliszka SR, McCracken JT, Maas JW. Catecholamines in attention-deficit hyperactivity disorder: current perspectives. J Am Acad Child Adolesc Psychiatr 1996;35:264–72. [4] Kent L, Green E, Hawi Z, Kirley A, Dudbridge F, Lowe N, et al. Association of the paternally transmitted copy of common valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD. Mol Psychiatr 2005;10:939–43. [5] Lanktree M, Muglia P, Squassina A, Krinsky M, Jain U, Macciardi F, et al. A potential role for brain derived neurotrophic factor (BDNF) in adult adhd (abstracts for the XIIth world congress of psychiatric genetics). Am J Med Gent 2004;130B:96–7. [6] Xu X, Mill J, Zhou K, Brookes K, Chen C, Asherson P. Familybased association study between brain-derived neurotrophic factor gene polymorphisms and attention deficit hyperactivity disorder (abstracts for XIII world congress on psychiatric genetics). Am J Med Gent 2005;138B:53. [7] Tsai SJ. Attention-deficit hyperactivity disorder and brainderived neurotrophic factor: a speculative hypothesis. Med Hypotheses 2003;60:849–51. [8] Wurster AL, Tanaka T, Grusby MJ. The biology of Stat4 and Stat6. Oncogene 2000;19:2577–84. [9] Takeda K, Kishimoto T, Akira S. STAT6: its role in interleukin 4-mediated biological functions. J Mol Med 1997;75: 317–26. [10] Foster PS. STAT6: an intracellular target for the inhibition of allergic disease. Clin Exp Allergy 1999;29:12–6. [11] De-Fraja C, Conti L, Magrassi L, Govoni S, Cattaneo E. Members of the JAK/STAT proteins are expressed and regulated during development in the mammalian forebrain. J Neurosci Res 1998;54:320–30. [12] De-Fraja C, Conti L, Govoni S, Battaini F, Cattaneo E. STAT signalling in the mature and aging brain. Int J Dev Neurosci 2000;18:439–46. [13] Cattaneo E, Conti L, De-Fraja C. Signalling through the JAKSTAT pathway in the developing brain. Trends Neurosci 1999;22:365–9. [14] Yukawa K, Iso H, Tanaka T, Tsubota Y, Owada-Makabe K, Bai T, et al. Down-regulation of dopamine transporter and
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
abnormal behavior in STAT6-deficient mice. Int J Mol Med 2005;15:819–25. Yukawa K, Tanaka T, Owada-Makabe K, Tsubota Y, Bai T, Maeda M, et al. Reduced prepulse inhibition of startle in STAT6-deficient mice. Int J Mol Med 2005;16:673–5. Sagvolden T, Russell VA, Aase H, Johansen EB, Farshbaf M. Rodent models of attention-deficit/hyperactivity disorder. Biol Psychiatr 2005;57:1239–47. Spencer T, Biederman J, Wilens T. Pharmacotherapy of attention deficit hyperactivity disorder. Child Adolesc Psychiatr Clin N Am 2000;9:77–97. Jucaite A, Fernell E, Halldin C, Forssberg H, Farde L. Reduced midbrain dopamine transporter binding in male adolescents with attention-deficit/hyperactivity disorder: association between striatal dopamine markers and motor hyperactivity. Biol Psychiatr 2005;57:229–38. Taylor E. Developmental neuropsychopathology of attention deficit and impulsiveness. Dev Psychopathol 1999;11: 607–28. Holden RJ, Pakula IS. Immunological influences in attention-deficit disorder and schizophrenia; is there a link between these two conditions? Med Hypotheses 1995;45: 575–87. Mittleman BB, Castellanos FX, Jacobsen LK, Rapoport JL, Swedo SE, Shearer GM. Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease. J Immunol 1997;159: 2994–9. Segman RH, Meltzer A, Gross-Tsur V, Kosov A, Frisch A, Inbar E, et al. Preferential transmission of interleukin-1 receptor antagonist alleles in attention deficit hyperactivity disorder. Mol Psychiatr 2002;7:72–4. Zhang WJ, Thompson JL, Chorney MJ, Koltun WA. Phenotyping of IL4-induced nuclear Stat6 activity in humans: quantitation after gel shift assay using immortalized cell lines. Oncol Rep 2003;10:1281–8. Amoli M, Ollier WE, Hajeer AH. A novel PCR-RFLP assay for the detection of a polymorphism in the 30 of STAT6 gene. Genes Immun 2000;1:349–50. Tamura K, Arakawa H, Suzuki M, Kobayashi Y, Mochizuki H, Kato M, et al. Novel dinucleotide repeat polymorphism in the first exon of the STAT-6 gene is associated with allergic diseases. Clin Exp Allergy 2001;31:1509–14.
http://intl.elsevierhealth.com/journals/mehy
Signal transducer and activator of transcription 6 (STAT6) and attention-deficit hyperactivity disorder: A speculative hypothesis Shih-Jen Tsai
*
Department of Psychiatry, Taipei Veterans General Hospital, Taiwan Division of Psychiatry, School of Medicine, National Yang-Ming University, Taiwan Received 9 May 2006; accepted 11 May 2006
Summary Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by hyperactivity, impulsiveness and inattention that begins in childhood. The underlying pathogenesis of this disorder is still unknown, although pharmacological, genetic and neuroimaging studies suggest that dopamine transportation may be implicated in the pathogenesis of ADHD. Signal transducer and activator of transcription 6 (STAT6), similar to other members of the signal transducer and activator of transcription family of proteins, is an important molecule in the induction and regulation of the immune response. Animal studies have demonstrated that STAT6 is highly expressed in the CNS, especially in the developing brain. Recent studies have demonstrated that STAT6-deficient mice exhibit increased locomotor activity and decreased levels of dopamine transporter expression in the striatum, when compared with the wild-type. From these findings, and evidence from other studies, it can be proposed that STAT6 may be implicated in the pathogenesis of ADHD. Several proposals to test this hypothesis are suggested; attempts to prove the STAT6–ADHD hypothesis may provide a new direction that elucidates the pathogenesis of and a treatment for ADHD. c 2006 Elsevier Ltd. All rights reserved.
Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder with onset at preschool age. The core symptoms include hyperactivity, impulsive, and inattention and it is associated with substantial life impairments and sometimes persists into adulthood. Although the biological basis of ADHD is still unknown, recent studies have suggested that this disorder is highly * Department of Psychiatry, Taipei Veterans General Hospital, No. 201 Shih-Pai Road, Section 2, 11217 Taipei, Taiwan. Tel.: +886 2 28757027x276; fax: +886 2 28725643. E-mail address: [email protected].
heritable and may be associated with neurobiological deficits in the prefrontal cortex and related subcortical systems [1]. Moreover, the effectiveness of stimulants, along with animal models of hyperactivity, point to catecholamine (dopamine and norepinephrine) circuit dys-regulation as at least one source of ADHD brain dysfunction [2,3]. Although the ‘‘catecholamine hypothesis’’ has been the major theory for the pathogenesis of ADHD, it cannot successfully account for the underlying pathophysiology. In this way, hypotheses about the cause of ADHD have evolved from simple one-cause theories to theories that describe
0306-9877/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2006.05.019
1342 a complex and multifactorial disorder [2]. For example, recent family-based genetic studies have demonstrated that brain-derived neurotrophic factor (BDNF) genetic variation is associated with ADHD susceptibility [4–6]. This supports the hypothesis that BDNF is involved in the pathogenesis of ADHD [7]. Although many hypotheses exist to describe the aetiology of ADHD, no one hypothesis satisfactorily accounts for all cases. Here, I propose that signal transducer and activator of transcription 6 (STAT6) may be implicated in the pathogenesis of ADHD. STAT6, similar to other members of the signal transducer and activator of transcription (STAT) family of proteins, provides a direct link between the cytokine receptors and cytokine-induced gene transcription. STAT6 specifically mediates signals that emanate from interleukin 4 (IL-4) receptors [8]. As an important molecule in the induction and regulation of the immune response, STAT6 has been implicated in the pathogenesis of allergic and inflammatory diseases [9,10]. In animal studies, De-Fraja and colleagues demonstrated that in the adult rat brain, STAT6 is expressed in the cortex, basal forebrain and hippocampus, while in the developing rat brain, high levels of STAT6 were found in striatum, cortex and hippocampus [11,12]. This suggests that STAT6 may play an important role in brain function and brain development [13]. This notion is further supported by a recent study by Yukawa and colleagues, who used a battery of murine behavioural analyses of STAT6-deficient mice, and suggested that STAT6-deficient mice may provide crucial information to the underlying pathophysiology of mental illness [14,15]. These findings from behavioural testing in STAT6-deficient mice, as well as evidence from other studies suggest that STAT6 may play a role in the pathogenesis of ADHD. Some evidences to support this hypothesis are suggested below. Firstly, in an animal study of genetically-modified STAT6-deficient mice, increased locomotor activity was observed compared to controls [14]. This mimics the fundamental behavioural characteristics of ADHD (face validity) [16]. Secondly, in the STAT6-deficient mouse, a reduced level of dopamine transporter (DAT) expression in the striatum was found when compared with the wild-type [14]. Dopamine transporters are the site of primary action of the stimulants that are known to be effective in the treatment of ADHD [17]. A recent positron emission tomography (PET) study demonstrated lower binding to DAT in the midbrain of adolescents with ADHD [18]. Furthermore, genetic studies had suggested association between ADHD and the 10-repeat allele of a
Tsai 40 base pair variable number of tandem repeats polymorphism of DAT gene [2]. Thirdly, ADHD is a common neurodevelopmental disorder that begins in childhood [19]. Genes, such as STAT6, are highly expressed in developing brains and may be involved in brain development [11–13], and are thus possibly important etiological factors in ADHD. Finally, immune system dys-regulation has been implicated in the pathogenesis of ADHD [20,21]. In a genetic association study, a preferential transmission of interleukin-1 receptor antagonist alleles in ADHD patients has been demonstrated [22]. This finding points to a role for brain cytokine activity in the pathogenesis of ADHD. STAT6, which provides a direct link between the cytokine receptors and cytokine-induced gene transcription, may bring about ADHD pathogenesis through immune regulation. The above evidence suggests that STAT6 plays a role in the pathogenesis of ADHD. In order to test this hypothesis, several proposals are presented in this paper. Firstly, the IL4-induced STAT6 signaling pathway is active in a variety of cell types and there are large quantitative differences in DNAbinding activities of IL4-induced STAT6, which is useful for phenotyping activated STAT6 in normal and diseased statuses. The recently-developed semi-quantitative methodology for testing STAT6 activities [23] could be used in lymphoblastoid cell lines from ADHD subjects to test for abnormalities in STAT6 activities. Secondly, molecular genetic studies show ADHD to be a common, multifactorial disorder with significant genetic contributions [2]. Common genetic polymorphisms, which are related to STAT6 expression, such as G2964A polymorphism [24] and dinucleotide (GT) repeat in exon 1 [25] of the STAT6 gene may be related to the risk, the clinical manifestations or the endophenotypes (e.g. central dopamine transporter density) of ADHD. Thirdly, most studies support stimulants as the best available pharmacotherapy for the treatment of children with ADHD. The effects of stimulants such as methylphenidate on the locomotor activity of STAT6-deficient mice may help to confirm a theoretical rationale for STAT6 in ADHD. Attempts to prove the STAT6–ADHD hypothesis may lead investigators in a new direction of study of the pathogenesis of ADHD and the development of an effective intervention for this disorder.
References [1] Spencer TJ, Biederman J, Wilens TE, Faraone SV. Overview and neurobiology of attention-deficit/hyperactivity disorder. J Clin Psychiatr 2002;63(suppl. 12):3–9.
Signal transducer and activator of transcription 6 (STAT6) and attention-deficit hyperactivity disorder 1343 [2] Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet 2005;366:237–48. [3] Pliszka SR, McCracken JT, Maas JW. Catecholamines in attention-deficit hyperactivity disorder: current perspectives. J Am Acad Child Adolesc Psychiatr 1996;35:264–72. [4] Kent L, Green E, Hawi Z, Kirley A, Dudbridge F, Lowe N, et al. Association of the paternally transmitted copy of common valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD. Mol Psychiatr 2005;10:939–43. [5] Lanktree M, Muglia P, Squassina A, Krinsky M, Jain U, Macciardi F, et al. A potential role for brain derived neurotrophic factor (BDNF) in adult adhd (abstracts for the XIIth world congress of psychiatric genetics). Am J Med Gent 2004;130B:96–7. [6] Xu X, Mill J, Zhou K, Brookes K, Chen C, Asherson P. Familybased association study between brain-derived neurotrophic factor gene polymorphisms and attention deficit hyperactivity disorder (abstracts for XIII world congress on psychiatric genetics). Am J Med Gent 2005;138B:53. [7] Tsai SJ. Attention-deficit hyperactivity disorder and brainderived neurotrophic factor: a speculative hypothesis. Med Hypotheses 2003;60:849–51. [8] Wurster AL, Tanaka T, Grusby MJ. The biology of Stat4 and Stat6. Oncogene 2000;19:2577–84. [9] Takeda K, Kishimoto T, Akira S. STAT6: its role in interleukin 4-mediated biological functions. J Mol Med 1997;75: 317–26. [10] Foster PS. STAT6: an intracellular target for the inhibition of allergic disease. Clin Exp Allergy 1999;29:12–6. [11] De-Fraja C, Conti L, Magrassi L, Govoni S, Cattaneo E. Members of the JAK/STAT proteins are expressed and regulated during development in the mammalian forebrain. J Neurosci Res 1998;54:320–30. [12] De-Fraja C, Conti L, Govoni S, Battaini F, Cattaneo E. STAT signalling in the mature and aging brain. Int J Dev Neurosci 2000;18:439–46. [13] Cattaneo E, Conti L, De-Fraja C. Signalling through the JAKSTAT pathway in the developing brain. Trends Neurosci 1999;22:365–9. [14] Yukawa K, Iso H, Tanaka T, Tsubota Y, Owada-Makabe K, Bai T, et al. Down-regulation of dopamine transporter and
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
abnormal behavior in STAT6-deficient mice. Int J Mol Med 2005;15:819–25. Yukawa K, Tanaka T, Owada-Makabe K, Tsubota Y, Bai T, Maeda M, et al. Reduced prepulse inhibition of startle in STAT6-deficient mice. Int J Mol Med 2005;16:673–5. Sagvolden T, Russell VA, Aase H, Johansen EB, Farshbaf M. Rodent models of attention-deficit/hyperactivity disorder. Biol Psychiatr 2005;57:1239–47. Spencer T, Biederman J, Wilens T. Pharmacotherapy of attention deficit hyperactivity disorder. Child Adolesc Psychiatr Clin N Am 2000;9:77–97. Jucaite A, Fernell E, Halldin C, Forssberg H, Farde L. Reduced midbrain dopamine transporter binding in male adolescents with attention-deficit/hyperactivity disorder: association between striatal dopamine markers and motor hyperactivity. Biol Psychiatr 2005;57:229–38. Taylor E. Developmental neuropsychopathology of attention deficit and impulsiveness. Dev Psychopathol 1999;11: 607–28. Holden RJ, Pakula IS. Immunological influences in attention-deficit disorder and schizophrenia; is there a link between these two conditions? Med Hypotheses 1995;45: 575–87. Mittleman BB, Castellanos FX, Jacobsen LK, Rapoport JL, Swedo SE, Shearer GM. Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease. J Immunol 1997;159: 2994–9. Segman RH, Meltzer A, Gross-Tsur V, Kosov A, Frisch A, Inbar E, et al. Preferential transmission of interleukin-1 receptor antagonist alleles in attention deficit hyperactivity disorder. Mol Psychiatr 2002;7:72–4. Zhang WJ, Thompson JL, Chorney MJ, Koltun WA. Phenotyping of IL4-induced nuclear Stat6 activity in humans: quantitation after gel shift assay using immortalized cell lines. Oncol Rep 2003;10:1281–8. Amoli M, Ollier WE, Hajeer AH. A novel PCR-RFLP assay for the detection of a polymorphism in the 30 of STAT6 gene. Genes Immun 2000;1:349–50. Tamura K, Arakawa H, Suzuki M, Kobayashi Y, Mochizuki H, Kato M, et al. Novel dinucleotide repeat polymorphism in the first exon of the STAT-6 gene is associated with allergic diseases. Clin Exp Allergy 2001;31:1509–14.