Role of histidine decarboxylase gene in the pathogenesis of Tourette syndrome

Abstract Tourette syndrome (TS) is caused by complex genetic and environmental factors and is characterized by tics. Histidine decarboxylase (HDC) mutation is a rare genetic cause with high penetrance in patients with TS. HDC‐knockout (KO) mice have similar behavioral and neurochemical abnormalities as patients with TS. Therefore, HDC‐KO mice are considered a valuable TS pathophysiological model as it reveals the underlying pathological mechanisms that cannot be obtained from patients with TS, thus advancing the development of treatment strategies for TS and other tic disorders. This review summarizes some of the recent research hotspots and progress in HDC‐KO mice, aiming to deepen our understanding of brain mechanisms relevant to TS. Furthermore, we encapsulate the possible brain nerve cell changes in HDC‐KO mice and their potential roles in TS to provide multiple directions for the future research on tics.


INTRODUCTION
Tourette syndrome (TS) is a childhood-onset disorder defined by abnormal developments in the cortico-subcortical and intracortical neural networks that control motor output and sensory input (Martino et al., 2015). It is associated with congenital dysplasia of the nervous system and is characterized by motor and vocal tics, as well as sensory and cognitive symptoms (Robertson et al., 2009). Tics are sudden, transient, repetitive, and semiautonomous movements or behaviors that help relieve local discomfort or tension. The motor pattern of forms, including shouting obscenities, hitting, or biting, and occur in adulthood. TS has high comorbidity rates with other neurodevelopmental disorders of childhood, such as obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) (Leckman, 2002). Copy number variation (CNV) analysis supports the genetic commonality between TS and autistic spectrum disorders (ASD) (Fernandez et al., 2012). Furthermore, learning disabilities and mood and anxiety disorders are common in patients with TS (Jurič et al., 2016).
The comorbidities of TS and other psychiatric disorders suggest that the etiology and pathophysiology of TS may be universally applicable to a wide range of psychiatric diseases.
TS is most likely caused by a variety of genetic and environmental factors and presents with obvious genetic heterogeneity (Liu et al., 2020). Evidence based on familial aggregation studies showed that the risk for first-degree relatives is significantly higher than that for individuals in the general population (Pauls et al., 1981;Pauls et al., 1991). In twin studies, 53−56% monozygotic twins were concordant for TS, whereas only 8% of dizygotic twins were concordant for TS (Liu et al., 2020;Price et al., 1985). Although these studies indicate that genetic factors play a significant role in TS etiology, the exact genetic risk remains unknown. TS is polygenic, involving multiple common risk variants accompanied by rare, inherited, or de novo mutations. Genome-wide, candidate gene, and CNV studies on TS etiopathogenesis have revealed multiple gene variants, including dopaminergic (DRD2,DRD4,DAT1) (Díaz-Anzaldúa et al., 2004;Herzberg et al., 2010;Tarnok et al., 2007), serotonergic (HTR1A, HTR2C) (Dehning et al., 2010;Lam et al., 1996), glutamatergic (SLC1A3) (Adamczyk et al., 2011), synapse developmental and functional (SLITRK1, NLGN4, and NRXN1) (Abelson et al., 2005;Lawson-Yuen et al., 2008;Nag et al., 2013), and neurotransmitter receptor (GRIN2b, HDC) (Ercan-Sencicek et al., 2010). However, because of the small sample size, the restricted number of variants in each study, and the inherent difficulties of riskgene studies involving genetically heterogeneous disorders, no individual candidate gene has met the statistical criteria of TS risk factors.
Nevertheless, these potential genes might provide clues to the neurobiology of TS.
The histidine decarboxylase gene (HDC) has been the focus of TS research in recent years. We have investigated the role of the histidine decarboxylase gene (HDC) in TS susceptibility in the Chinese Han population (Dong et al., 2016), but the findings indicate an unlikely association between HDC and TS in the Chinese Han population. Here, we first introduce the discovery of HDC and the mutations that confer susceptibility to TS. Then the significance and difficulties of using HDC-

Mutations in HDC confers susceptibility to TS
HDC is a member of the group II decarboxylase family that encodes L-histidine decarboxylase and forms a homodimer that converts Lhistidine to histamine in a pyridoxal phosphate-dependent manner (Dong et al., 2016 (Fernandez et al., 2012). Furthermore, Karagiannidis et al. (2013) showed overtransmission of alleles for rs854150 and rs1894236 in the HDC region in a large sample of 520 families from seven European countries, suggesting that rs1894236 may be directly involved in the transcriptional regulation of HDC. Taken together, these studies indicated that HDC confers susceptibility to TS, supporting the hypothesis that histamine dysregulation is strongly associated with TS.

HDC-KO mice as a pathophysiological model of TS
Because of the solid evidence for the role of histamine dysregulation in neuropsychiatric disorders, HDC-KO mice have received increasing attention. HDC−/− and heterozygote mice show increased ticlike stereotypies and D 2 +D 3 receptor dysregulation, recapitulating the core phenomenology of TS. Furthermore, preconditioning with haloperidol or injection with histamine alleviates the stereotypies of HDC-KO mice, indicating that the behavioral and neurochemical abnormalities are similar to patients with TS with HDC W317X mutations (Baldan et al., 2014). These findings demonstrate the validity of HDC-KO mouse model for TS. One of its weakness is that stereotypies occur after pharmacological challenges, complicating the use of HDC−/− mice to discover new therapies (Xu et al., 2015). Histamine-deficient mice treated with a stimulant present persistent and progressive enhancement of locomotor and stereotypic behaviors, such as sniffing, biting, and rearing, and has thus been proposed as a model of human tics (Kubota et al., 2002). However, Xu et al. (2015) induced tic-like stereotypes in the HDC−/− model stimulated by cued fear conditioning, suggesting that the stress-induced stereotypy phenotype is more suitable for future pharmacological studies due to the presence of enhanced tic-like behavior without pharmacological challenge (Baldan et al., 2014).
Studies on neuropsychiatric disorders are hampered by the neurobiology of the brain and the ethical or practical difficulties presented by invasive technologies. There are limitations in our recognition of details of the molecular biology and physiology in the human brain, although noninvasive technologies to study the structure and function of the human brain are being developed rapidly (Nestler & Hyman, 2010). The use of highly explicit and rare mutations to establish animal models has an important value for the study of the pathophysiology of TS. However, differences in species prevent the full replication of the core traits of patients with neuropsychiatric disorders, such as reading and thinking, as these are unique to humans. The key characteristics of the disease reproduced in animal models may not be specifically identified and quantified; therefore, trying to study all aspects of the disease in animal models is impractical (Pittenger, 2020). Although some important aspects of TS in HDC-KO mice, such as repetitive, ticlike behaviors, can be observed and quantified, it is impossible to assess whether they are associated with the premonitory urges that characterize tics (Pittenger, 2017). Our knowledge of the pathophysiology of TS is still limited. However, the corticostriatal circuits in mice and humans are broadly similar in tic disorders, and multiple levels of parallelism have been established between HDC-KO mice and human HDC W317X mutation (Pittenger, 2020). Therefore, a careful study of pathophysiological processes in mice may shed light on the pathogenesis of human diseases.

1.3
Changes in dopamine, histamine, and their receptors in HDC-KO mice
A recent study shows that the HA level of HDC−/− mice is significantly decreased, whereas that of DA is significantly increased (Baldan et al., 2014). The striatal DA turnover in HDC-KO mice is increased (Dere et al., 2003). Baldan et al. (2014) used positron emission tomography to examine DA receptors in vivo because DA cannot be directly detected in humans, and the compensatory changes in the dopamine receptors reflect the maladjustment of dopaminergic regulation within the basal ganglia. They found that the dopamine D 2 +D 3 receptor within the basal ganglia is dysregulated in patients with TS having the W317X mutation (Baldan et al., 2014). They focused on the dopamine D 2 +D 3 receptors because D 2 antagonists are the most effective pharmacotherapy for TS, and dopamine D 3 receptors (D 3 R) may function as inhibitory autoreceptors (Jurič et al., 2016). Decreased striatal D 2 +D 3 receptor binding and increased substantia nigra D 2 +D 3 receptor binding may indicate a cellular response to a chronic increase in striatal DA (Stanwood et al., 2000). Elevated dopamine receptors in the substantia nigra were found in patients with mutated HDC and HDC-deficient mice, further supporting the disorder of DA in vivo. These studies were the first to demonstrate the direct relationship between the change in histaminergic nerve transmission and the dopaminergic regulation of basal ganglia neural circuits in humans (Baldan et al., 2014).
Striatum medium spiny neurons (MSNs) can be divided into D1 receptor-expressing (dMSNs) and D 2 receptor-expressing (iMSNs) ones. Striatonigral neurons expressing the D 1 dopamine receptor (D 1 R) and striatopallidal neurons expressing the D 2 dopamine receptor (D 2 R) provide excitatory and inhibitory feedback to the cortex, respectively. The dynamic imbalance between the two pathways is considered core to the TS pathogenesis (Albin & Mink, 2006;McBride & Parker, 2015). Elevated DA levels in HDC-KO mice may affect the signal transduction of D 1 R and D 2 R. As a rare TS pathophysiological model,

Changes in histamine and histamine receptor
Histamine is an important monoamine neurotransmitter in the brain. Histamine was not detected in the striatum of HDC−/− mice, which indicates a chronic deficiency (Baldan et al., 2014). To make the effect of histamine deletion more pronounced, histaminergic neurons in the TMN of the hypothalamus of normally developing mice were specifically ablated or chemically silenced, lacking neurons or peripheral histamine throughout the process. Results showed that the ablationgroup mice have increased grooming and grooming times, slightly lower anxiety, and increased tendency of fear, but the exploratory movement and shock pulse before inhibition (PPI) were not changed.
Further, the grooming of the histaminergic neuron inhibition group was also significantly increased. These results support the key role of TMN in regulating repetitive behavior .
Moreover, after TMN inhibition, the striatum and cortex activities in the brain of mice were enhanced and the activation of dorsal striatum neurons after TMN inactivation led to significant grooming . After the injection of histamine into the brain of the histaminergic neuronal inhibitory-group mice, the movement was decreased, and the elevated grooming was reversed, which was similar to the conclusion of studies where the stereotypic behavior was produced by the activation of histaminergic signaling in the dorsal striatum of the HDC-KO mice (Baldan et al., 2014;. These confirmed that acute histamine deficiency mediates these behavioral effects, and that pathogenesis is acute. The expression of H 1 R mRNA in the striatum of HDC-KO mice was quantitatively determined using in situ hybridization. The expression of H 1 R mRNA did not change significantly, and another mRNA expression study showed no significant increase in its expression in the hippocampus of HDC−/− mice La Piana et al., 2012). In another study, radiation ligand binding and in situ hybridization were used to detect the H 2 R in HDC-knockout mice, and they found that H 2 R mRNA was not altered in the striatum (Rapanelli, Frick, Pogorelov et al., 2017). In contrast, mRNA detection in the striatum homogenate of Recent studies suggest that the dysregulation of the H 3 receptor in the basal ganglia leads to the related phenomenology of tics in HDC-KO mice (Pittenger, 2020). H 3 R has been presented as a potential and important regulator of signal transduction in MSNs (Moreno et al., 2011). Therefore, the H 3 receptor has become the current focus of pathophysiology studies and a potential therapeutic target for tic disorders and related diseases (Pittenger, 2020 (Schlicker et al., 1994). In addition, the H 3 R antagonist JNJ5207852 can block this stereotype after the use of RAMH and immepip, further confirming the effects of H 3 R (Rapanelli, Frick, Pogorelov et al., 2017). These reports were the first to demonstrate a direct relationship between H 3 R activation and ticlike phenomenology in a pathophysiology-based TS model (Rapanelli, Frick, Pogorelov et al., 2017).
The majority of H 3 R in the striatum is postsynaptic, which cascades with signals from intracellular striatal MSNs in a complex and cell-type-specific manner (Ferrada et al., 2008;Ferrada et al., 2009;Moreno et al., 2011;Rapanelli et al., 2016). In vitro studies have demonstrated that H 3 R can regulate MAPK signaling via heterodimerization with dopamine D 2 receptor (Ferrada et al., 2008;Ferrada et al., 2009;Moreno et al., 2011). Previous studies have shown that both H 3 R mRNA expression and radio-ligand binding are upregulated in the striatum of HDC−/− mice (Rapanelli, Frick, Pogorelov et al., 2017).  Because of recent studies, microglia have taken on new roles in brain development, homeostasis, and plasticity (Paolicelli et al., 2011;Ziv et al., 2006). Particularly, microglia prune synapses, which is necessary to form brain circuits and normal connections during normal devel-opment in mice (Ji et al., 2013;Zhan et al., 2014). Microglial dysregulation has also been observed in TS. Immunohistochemical studies on the postmortem brain of TS patients showed an elevated count of cells of the macrophage/microglia lineage and activated morphological features in the caudate. These results suggest that brain microglia activation might be the underlying mechanism in the inflammatory changes observed in the brain (Lennington et al., 2016). but not in the motor cortex, and such regional differences were not observed in the microglia culture experiments in vitro.

Changes in nerve cells in the brain of
Microglia are phagocytes that infiltrate the brain during development and remodel synapses as the brain matures. Synaptic pruning by microglia is necessary for the formation of normal connectivity and brain circuitry (Schafer et al., 2012). A transient reduction in microglia during the early postnatal period and a deficient synaptic pruning in Cx3cr1 (expressed by microglia in the brain) have been observed in KO mice, which resulted in changes in the neuron-microglia communication. The deficient synaptic pruning is associated with repetitive behavioral phenotypes, deficits in social interaction, weak synaptic transmission, and decreased functional brain connectivity, which are thought to be associated with neurodevelopmental and neuropsychiatric disorders (Zhan et al., 2014).  found that Cx3cr1-KO mice present with excessive grooming, similar to HDC-KO mice.
As the deficiency in microglia-mediated synaptic pruning may lead to neurodevelopmental and neuropsychiatric disorders, it is necessary to study synaptic pruning in HDC-KO mice and other TS mouse models. Niimi et al. (1997) reported that HDC activity in the primary culture of rat diencephalon cells with no mast cells can be upregulated by LPS and IL-1β. In addition, our preliminary in situ hybridization studies with primary brain cultures of rat embryos showed that microglia-like cells were positive for HDC mRNA. To investigate whether microglia are the third compartment of histamine production in the brain, the HDC activity of microglia GMI 6-3 and microglia Ra2 in the presence or absence of LPS has been studied (Katoh et al., 2001). HDC activity increases after LPS stimulation in the microglia GMI 6-3 of mice. In addition, Northern blot analysis showed that the HDC mRNA expres-sion is induced in microglia GMI 6-3 treated with LPS, showing that certain microglial types in the brain can produce histamine. These studies indicate that histamine in the brain has a close and complex relationship with microglia. Therefore, the dysregulation mechanism of microglia plays an important role in the pathophysiology of HDC-KO mice ( Figure 2).

Oligodendrocyte
In the past two years, the H 3 receptor (H 3 R) has received increasing research attention. Some studies have showed that the imbalance in H 3 R in the basal ganglia leads to the correlational phenomenology in HDC−/− mice. The H 3 R in the striatum of HDC-KO mice was upregulated and still had constitutive activity without the ligand (Morisset et al., 2000;Pittenger, 2020). H3R, a member of the histamine receptor family, is highly expressed in the central nervous system and has been identified as a potential drug target for the treatment of neurological and psychiatric diseases, but its function in oligodendrocytes remains unknown.
In which is known as excitatory toxicity. Increasing evidence shows that glial cells in the brain, especially astrocytes, control the extracellular glutamate content and prevent excitatory toxicity. Due to the lack of extracellular metabolic pathways, glutamate, after being released into the synaptic cleft, is mainly taken up by glutamate transporters (GLT-1, GLAST) in astrocytes and converted into intracellular glutamine by glutamine synthetase (GS). Subsequently, the glutamine is transported back to glutamate or γ-aminobutyric acid (GABA) neurons as raw material for glutamate and GABA synthesis. Rodriguez et al. (1989) reported that the GS activity in cerebellar astrocytes can be elevated by histamine. Moreover, histamine can upregulate GLT-1, which provides another key link in glutamate metabolism by astrocytes via H1 receptor, thus reducing extracellular glutamate levels and playing a neuroprotective role in excitotoxicity and ischemic injury .
A study has speculated that the glutamate-glutamate cycle regulatory factor and glutamate transporters of astrocytes may function in histamine system protection and have a treatment effect via the removal of excess glutamate. This can reduce the excitatory toxicity in the early stages of cerebral ischemia, balance the glutamate synaptic transmission, and protect early neurons. However, further in vivo studies are needed to confirm this hypothesis. There is very little evidence for the interaction between histamine and astrocyte immunoregulation. A study has shown that histamine significantly amplifies the secre-tion of NGF (a neurotrophic factor) in astrocytes stimulated by the proinflammatory cytokine IL-6 and has a superposition effect with the proinflammatory cytokine IL-1β (Lipnik-Stangelj, 2006). Histamine is an important player in the interaction between astrocytes and proinflammatory cytokines, which may increase not only neuronal inflammation but also NGF production to counteract neuronal inflammation.
Histamine plays an important role in astrocyte activity, such as energy metabolism and immune response. Therefore, we believe that it plays an important role in regulating astrocyte function, which deserves further investigation using HDC-deficient mice (Jurič et al., 2016) ( Figure 2).

CONCLUSIONS
In summary, TS is a developmental neuropsychiatric disorder asso-

ACKNOWLEDGMENT
We thank all the people for their participation. This study is supported by the National Natural Science Foundation of China (81371499).

CONFLICT OF INTEREST
All authors claim that there are no conflicts of interest.

AUTHOR CONTRIBUTIONS
SL and XZ designed the project conception. LX, CZ, MZ, FC, and CG performed the literature search and analysis. LX wrote the manuscript with contribution from SL and XZ. All authors read and approved the final manuscript.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.