Histidine Decarboxylase Deficiency Causes Tourette Syndrome: Parallel Findings in Humans and Mice

Baldan, Lissandra Castellan; Williams, Kyle; Gallezot, Jean‐Dominique; Pogorelov, Vladimir M.; Rapanelli, Maximiliano; Crowley, Michael J.; Anderson, George M.; Loring, Erin; Gorczyca, Roxanne; Billingslea, Eileen; Wasylink, Suzanne; Panza, Kaitlyn E.; Ercan-Şençiçek, A. Gülhan; Krusong, Kuakarun; Leventhal, Bennett L.; Ohtsu, Hiroshi; Bloch, Michael H.; Hughes, Zoë A.; Krystal, John H.; Mayes, Linda C.; Araújo, Ivan de; Ding, Yu‐Shin; State, Matthew W.; Pittenger, Christopher

doi:10.1016/j.neuron.2013.10.052

Cited by 207 publications

(249 citation statements)

References 79 publications

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“…C, Ser(P) 9 -GSK3␤ was increased 15 min after RAMH in GFP-negative cells (presumptive D1-MSNs). SKF82958 had no effect on Ser(P) 9 -GSK3␤ and did not modulate the effect of RAMH (two-way ANOVA: main effect of RAMH: F [1,14] There was no effect of either drug (at this time point) on Ser(P) 9 -GSK3␤ in GFP-positive cells (presumptive D2-MSNs). n ϭ 6 SAL, 4 in other groups.…”

Section: Discussionmentioning

confidence: 85%

“…HDC protein is particularly concentrated in the striatum, suggesting an important role for HA there (19). We have shown loss of Hdc to lead to elevated striatal DA, increased tic-like stereotypies, and alterations in MAPK and Akt signaling (1,20,21).…”

mentioning

confidence: 85%

“…Because striatal HA fluctuates slowly, with a circadian pattern (1,7), this would predict circadian variation in the sensitivity to D1 agonist effects. Diurnal variation in psychostimulant effects has indeed been documented (50).…”

Section: H3r Regulation Of Mapk Msk and Rps6 -H3 Receptors Can Coupmentioning

confidence: 99%

“…The basal ganglia play a critical role in the regulation of cognition, motor control, motivated behavior, and habit learning as well as in the pathophysiology of a range of neuropsychiatric conditions, including Parkinson's disease, Tourette syndrome, and drug addiction (1)(2)(3)(4)(5)(6). Factors that modulate information flow through the basal ganglia circuitry are therefore of broad importance.…”

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confidence: 99%

“…This is seen, for example, at high psychostimulant doses or after repeated injections (1,38). Specific D1 activation with agents such as SKF82958 does not typically produce high levels of stereotypy, but it is possible that simultaneous RAMH administration might potentiate stereotypy and reduce locomotion by this mechanism.…”

mentioning

confidence: 99%

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The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons

Rapanelli¹,

Frick²,

Horn³

et al. 2016

Journal of Biological Chemistry

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The basal ganglia have a central role in motor patterning, habits, motivated behaviors, and cognition as well as in numerous neuropsychiatric disorders. Receptors for histamine, especially the H3 receptor (H3R), are highly expressed in the striatum, the primary input nucleus of the basal ganglia, but their effects on this circuitry have been little explored. H3R interacts with dopamine (DA) receptors ex vivo; the nature and functional importance of these interactions in vivo remain obscure. We found H3R activation with the agonist R-(-)-␣-methylhistamine to produce a unique time-and cell type-dependent profile of molecular signaling events in the striatum. H3 agonist treatment did not detectably alter extracellular DA levels or signaling through the cAMP/DARPP-32 signaling pathway in either D1-or D2-expressing striatal medium spiny neurons (MSNs). In D1-MSNs, H3 agonist treatment transiently activated MAPK signaling and phosphorylation of rpS6 and led to phosphorylation of GSK3␤-Ser 9 , a novel effect. Consequences of H3 activation in D2-MSNs were completely different. MAPK signaling was unchanged, and GSK3␤-Ser 9 phosphorylation was reduced. At the behavioral level, two H3 agonists had no significant effect on locomotion or stereotypy, but they dramatically attenuated the locomotor activation produced by the D1 agonist SKF82958. H3 agonist co-administration blocked the activation of MAPK signaling and the phosphorylation of rpS6 produced by D1 activation in D1-MSNs, paralleling behavioral effects. In contrast, GSK3␤-Ser 9 phosphorylation was seen only after H3 agonist treatment, with no interactive effects. H3R signaling has been neglected in models of basal ganglia function and has implications for a range of pathophysiologies.The basal ganglia play a critical role in the regulation of cognition, motor control, motivated behavior, and habit learning as well as in the pathophysiology of a range of neuropsychiatric conditions, including Parkinson's disease, Tourette syndrome, and drug addiction (1-6). Factors that modulate information flow through the basal ganglia circuitry are therefore of broad importance. The roles of dopamine (DA) 4 and acetylcholine in the regulation of striatal information processing have been extensively studied. Histamine (HA) is produced in the tuberomamillary nucleus of the posterior hypothalamus; these neurons project broadly throughout the brain, including to the striatum (7). HA receptors are prominent throughout the basal ganglia (7,8), but their function in modulating this circuitry is not well understood, and very few studies have examined their functional importance in vivo (9).The striatum (equivalent to the caudate and putamen in primates) is the largest nucleus of the basal ganglia and the primary site of cortical and thalamic input. Its principal cells, the medium spiny neurons (MSNs), can be divided into two subpopulations based on their projections. Striatonigral or "direct pathway" neurons preferentially express the D1 DA receptor and have a net disinhibitory effect on t...

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Section: Discussionmentioning

confidence: 85%

mentioning

confidence: 85%

Section: H3r Regulation Of Mapk Msk and Rps6 -H3 Receptors Can Coupmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons

Rapanelli¹,

Frick²,

Horn³

et al. 2016

Journal of Biological Chemistry

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Identification of candidate genes involved in the etiology of sporadic Tourette syndrome by exome sequencing

Eriguchi

Kuwabara

Inai

et al. 2017

American J of Med Genetics Pt B

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Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by chronic motor and vocal tics. Although there is a large genetic contribution, the genetic architecture of TS remains unclear. Exome sequencing has successfully revealed the contribution of de novo mutations in sporadic cases with neuropsychiatric disorders such as autism and schizophrenia. Here, using exome sequencing, we investigated de novo mutations in individuals with sporadic TS to identify novel risk loci and elucidate the genetic background of TS. Exome analysis was conducted for sporadic TS cases: nine trio families and one quartet family with concordant twins were investigated. Missense mutations were evaluated using functional prediction algorithms, and their population frequencies were calculated based on three public databases. Gene expression patterns in the brain were analyzed using the BrainSpan Developmental Transcriptome. Thirty de novo mutations, including four synonymous and four missense mutations, were identified. Among the missense mutations, one in the rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR)-coding gene (rs140964083: G > A, found in one proband) was predicted to be hazardous. In the three public databases analyzed, variants in the same SNP locus were absent, and variants in the same gene were either absent or present at an extremely low frequency (3/5,008), indicating the rarity of hazardous RICTOR mutations in the general population. The de novo variant of RICTOR may be implicated in the development of sporadic TS, and RICTOR is a novel candidate factor for TS etiology.

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Genetic association signal near NTN4 in Tourette syndrome

Paschou

Gerber

et al. 2014

Annals of Neurology

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Tourette Syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (SNPs)(p<10−3) from the recent TS genome-wide association study (GWAS) in 609 independent cases and 610 ancestry-matched controls. Only rs2060546 on chromosome 12q22 (p=3.3×10−4) remained significant after Bonferroni correction. Meta-analysis with the original GWAS yielded the strongest association to date (p=5.8×10−7). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case/control status (p=0.042), suggesting that many of these variants are true TS risk alleles.

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Histidine Decarboxylase Deficiency Causes Tourette Syndrome: Parallel Findings in Humans and Mice

Cited by 207 publications

References 79 publications

The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons

The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons

Identification of candidate genes involved in the etiology of sporadic Tourette syndrome by exome sequencing

Genetic association signal near NTN4 in Tourette syndrome

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