Histidine Decarboxylase Knockout Research Articles

Histamine Signaling Is Essential for Tissue Macrophage Differentiation and Suppression of Bacterial Overgrowth in the Stomach.

Histamine in the stomach traditionally is considered to regulate acid secretion but also has been reported to participate in macrophage differentiation, which plays an important role in tissue homeostasis. Therefore, this study aimed to uncover the precise role of histamine in mediating macrophage differentiation and in maintaining stomach homeostasis. Here, we expand on this role using histidine decarboxylase knockout (Hdc-/-) mice with hypertrophic gastropathy. In-depth invivo studies were performed in Hdc-/- mice, germ-free Hdc-/- mice, and bone-marrow-transplanted Hdc-/- mice. The stomach macrophage populations and function were characterized by flow cytometry. To identify stomach macrophages and find the new macrophage population, we performed single-cell RNA sequencing analysis on Hdc+/+ and Hdc-/- stomach tissues. Single-cell RNA sequencing and flow cytometry of the stomach cells of Hdc-/- mice showed alterations in the ratios of 3 distinct tissue macrophage populations (F4/80+Il1bhigh, F4/80+CD93+, and F4/80-MHC class IIhighCD74high). Tissue macrophages of the stomachs of Hdc-/- mice showed impaired phagocytic activity, increasing the bacterial burden of the stomach and attenuating hypertrophic gastropathy in germ-free Hdc-/- mice. The transplantation of bone marrow cells of Hdc+/+ mice to Hdc-/- mice recovered the normal differentiation of stomach macrophages and relieved the hypertrophic gastropathy of Hdc-/- mice. This study showed the importance of histamine signaling in tissue macrophage differentiation and maintenance of gastric homeostasis through the suppression of bacterial overgrowth in the stomach.

Disruption of histamine/H1R-STAT3-SLC7A11 axis exacerbates doxorubicin-induced cardiac ferroptosis

Doxorubicin (DOX) is widely used in the treatment of various cancers, increasing the great risk of adverse cardiovascular events, while the clinical intervention effect is not ideal. Histamine has been documented to participate in pathophysiological processes of cardiovascular diseases and inflammation-associated carcinogenesis. However, the potential roles of histamine in antitumor-related cardiotoxicity have not been fully elucidated. In this study, cardiomyocytes (hiPSC-CMs, HL-1 cells) and mice were treated with DOX to establish DOX-induced cardiotoxicity (DIC) models. Histidine decarboxylase knockout mice (HDC−/−) mice and histamine 1 receptor (H1R) antagonist were used to explore the effect of histamine/H1R signaling on DIC. Our results demonstrated that histamine deficiency or pharmaceutical inhibition of H1R accelerated myocardial ferroptosis, which is responsible for the aggravated DIC both in vivo and in vitro, while the supplementation of exogenous histamine reversed these changes. Our data revealed that the dysfunction of histamine/H1R signaling repressed the activation of transducer and activator of transcription 3 (STAT3), accompanying with decreased expression of solute carrier family7member11 (SLC7A11), a major modulator of ferroptosis. Conclusively, the disruption of histamine/H1R axis triggered ferroptosis and exacerbated DIC possibly by modulating STAT3-SLC7A11 pathway. Our findings point to a potential therapeutic target for DIC and provide more consideration on the usage of antihistamine drugs.

Abnormal histidine metabolism promotes macrophage lipid accumulation under Ox-LDL condition

Distinct macrophage populations exert highly heterogeneity and perform various functions, among which, a crucial function of lipid metabolism is highlighted. However, the role of histidine metabolism disorder in macrophage lipid metabolism remains elusive. Addressed this question, we sorted and cultured the bone marrow-derived macrophages (BMDMs) of histidine decarboxylase (Hdc) knockout (Hdc−/-) mice with an in vitro oxidized low-density lipoprotein (ox-LDL) model, and detected the intracellular lipids by Oil Red O staining as well as lipid probe staining. Astemizole, a canonical and long-acting histamine H1 receptor (H1R) antagonist, was applied to elucidate the impact of antagonizing the H1R-dependent signaling pathway on macrophage lipid metabolism. Subsequently, the differential expressed genes were screened and analyzed in the bone marrow-derived CD11b+ immature myeloid cells of Hdc−/- and Hdc+/+ mice with a high fat diet by the microarray study. The expression levels of cholesterol metabolism-related genes were examined by qRT-PCR to explore underlying mechanisms. Lastly, we used a high-sensitivity histidine probe to detect the intracellular histidine in the BMDMs after oxidative stress. The results revealed that histidine metabolism disorder and histamine deficiency aggravated lipid accumulation in the ox-LDL-treated BMDMs. The expression level of H1R gene in the BMDMs was down-regulated after ox-LDL stimulation. The disruption of the H1R-dependent signaling pathway by astemizole further exacerbated ox-LDL-induced lipid deposition in the BMDMs partly by up-regulating scavenger receptor class A (SR-A) for lipid intake, down-regulating neutral cholesteryl ester hydrolase (nCEH) for cholesterol esterification and down-regulating ATP-binding cassette transporters A1 (ABCA1) and ABCG1 for reverse cholesterol transport. The intracellular histidine increased under ox-LDL condition, which was further increased by Hdc knockout. Collectively, these results partially reveal the relationship between histidine metabolism and lipid metabolism in the BMDMs and offer a novel strategy for lipid metabolism disorder-associated diseases.

Histamine Deficiency Promotes Myofibroblasts Transformation from HDC-Expressing CD11b+ Myeloid Cells in Injured Hearts Post Myocardial Infarction.

Myocardial infarction (MI) is a significant contributor to the development of heart failure. Histidine decarboxylase (HDC), the unique enzyme that converts L-histidine to histamine, is highly expressed in CD11b+ immature myeloid cells. However, the relationship between HDC-expressing macrophages and cardiac myofibroblasts remains to be explained. Here, we demonstrate that the GFP (green fluorescent protein)-labeled HDC+CD11b+ myeloid precursors and their descendants could differentiate into fibroblast-like cells in myocardial interstitium. Furthermore, we prove that CD11b+Ly6C+ monocytes/macrophages, but not CD11b+Ly6G+ granulocytes, are identified as the main cellular source for bone marrow-derived myofibroblast transformation, which could be regulated via histamine H1 and H2 receptor-dependent signaling pathways. Using HDC knockout mice, we find that histamine deficiency promotes myofibroblast transformation from Ly6C+ macrophages and cardiac fibrosis partly through upregulating the expression of Krüppel-like factor 5 (KLF5). Taken together, our data uncover a central role of HDC in regulating bone marrow-derived macrophage-to-myofibroblast transformation but also identify a histamine receptor (HR)-KLF5 related signaling pathway that mediates myocardial fibrosis post-MI. CD11b+Ly6C+ monocytes/macrophages are the main cellular source for bone marrow-derived myofibroblast transformation. Histamine inhibits myofibroblasts transformation via H1R and H2R-dependent signaling pathways, and ameliorates cardiac fibrosis partly through upregulating KLF5 expression.

Tibialis anterior electromyographic bursts during sleep in histamine-deficient mice.

Antihistamine medications have been suggested to elicit clinical features of restless legs syndrome. The available data are limited, particularly concerning periodic leg movements during sleep, which are common in restless legs syndrome and involve bursts of tibialis anterior electromyogram. Here, we tested whether the occurrence of tibialis anterior electromyogram bursts during non-rapid eye movement sleep is altered in histidine decarboxylase knockout mice with congenital histamine deficiency compared with that in wild-type control mice. We implanted six histidine decarboxylase knockout and nine wild-type mice to record neck muscle electromyogram, bilateral tibialis anterior electromyogram, and electroencephalogram during the rest (light) period. The histidine decarboxylase knockout and wild-type mice did not differ significantly in terms of sleep architecture. In both histidine decarboxylase knockout and wild-type mice, the distribution of intervals between tibialis anterior electromyogram bursts had a single peak for intervals < 10s. The total occurrence rate of tibialis anterior electromyogram bursts during non-rapid eye movement sleep and the occurrence rate of the tibialis anterior electromyogram bursts separated by intervals < 10s were significantly lower in histidine decarboxylase knockout than in wild-type mice. These data do not support the hypothesis that preventing brain histamine signalling may promote restless legs syndrome. Rather, the data suggest that limb movements during sleep, including those separated by short intervals, are a manifestation of subcortical arousal requiring the integrity of brain histamine signalling.

Genetic lack of histamine upregulates dopamine neurotransmission and alters rotational behavior but not levodopa-induced dyskinesia in a mouse model of Parkinson’s disease

The brain histaminergic and dopaminergic systems closely interact, and some evidence also suggests significant involvement of histamine in Parkinson’s disease (PD), where dopaminergic neurons degenerate. To further investigate histamine-dopamine interactions, particularly in the context of PD, a genetic lack of histamine and a mouse model of PD and levodopa-induced dyskinesia were here combined. Dopaminergic lesions were induced in histidine decarboxylase knockout and wildtype mice by 6-hydroxydopamine injections into the medial forebrain bundle. Post-lesion motor dysfunction was studied by measuring drug-induced rotational behavior and dyskinesia. Striatal tissue from both lesioned and naïve animals was used to investigate dopaminergic, serotonergic and histaminergic biomarkers. Histamine deficiency increased amphetamine-induced rotation but did not affect levodopa-induced dyskinesia. qPCR measurements revealed increased striatal expression of D1 and D2 receptor, DARPP-32, and H3 receptor mRNA, and synaptosomal release experiments in naïve mice indicated increased dopamine release. A lack of histamine thus causes pre- and postsynaptic upregulation of striatal dopaminergic neurotransmission which may be reflected in post-lesion motor behavior. Disturbances or manipulations of the histaminergic system may thus have significant consequences for dopaminergic neurotransmission and motor behavior in both healthy and disease conditions. The findings also represent new evidence for the complex interplay between dopamine and histamine within the nigrostriatal pathway.

Disruption of histamine/H1R signaling pathway represses cardiac differentiation and maturation of human induced pluripotent stem cells

BackgroundThe efficiency and quality of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are crucial for regenerative medicine, disease modeling, drug screening, and the study of the development events during cardiac specification. However, their applications have been hampered by the differentiation efficiency, poor maturation, and high interline variability. Recent studies have reported that histamine plays important roles in hematopoietic stem cell proliferation and neutrophil maturation. However, its roles in cardiovascular tissue regeneration have not been thoroughly investigated. In the current study, we identified a novel physiological function of the histamine/histamine 1 receptor (H1R) signal in regulating the differentiation of hiPSC-CMs and heart development.MethodsTransgenic zebrafish model (cmlc2: mCherry) was treated with histamine and histamine receptor (HR) antagonists. Histological morphology and ultrastructure of zebrafish heart were measured. Histamine-deficient pregnant mice (HDC−/−) were treated with H1R antagonist (pyrilamine) by intragastric administration from E8.5 to E18.5. Cardiac histological morphology and ultrastructure were analyzed in neonatal mice, and cardiac function in adult mice was measured. In vitro, histamine and HR antagonists were administrated in the culture medium during hiPSC-CM differentiation at different stages. The efficiency and maturation of cardiac differentiation were evaluated. Finally, histamine-treated hiPSC-CMs were transplanted into ischemic myocardium to detect the possible therapeutic effect.ResultsAdministration of H1R antagonist during heart development induced cardiac dysplasia in zebrafish. Furthermore, using histidine decarboxylase (HDC) knockout mice, we examined abnormal swelling of myocardial mitochondria and autophagy formation under the condition of endogenous histamine deficiency. Histamine significantly promoted myocardial differentiation from human induced pluripotent stem cells (hiPSCs) with better structure and function via a H1R-dependent signal. The activation of histamine/H1R signaling pathway augmented hiPSC-derived cardiomyocyte (hiPSC-CM) differentiation through the ERK1/2-STAT3 signaling pathway. In addition, histamine-pre-treated hiPSC-CMs were transplanted into the ischemic hearts of myocardial injured mice and exhibited better survival and myocardial protection.ConclusionsThus, these findings indicated that histamine/H1R and its downstream signals were not only involved in cardiac differentiation but also provided a better survival environment for stem cell transplanted into ischemic myocardium.

Histamine deficiency facilitates coronary microthrombosis after myocardial infarction by increasing neutrophil-platelet interactions.

Neutrophil‐platelet interactions are responsible for thrombosis as well as inflammatory responses following acute myocardial infarction (AMI). While histamine has been shown to play a crucial role in many physiological and pathological processes, its effects on neutrophil‐platelet interactions in thromboinflammatory complications of AMI remain elusive. In this study, we show a previously unknown mechanism by which neutrophil‐derived histamine protects the infarcted heart from excessive neutrophil‐platelet interactions and redundant arterial thrombosis. Using histamine‐deficient (histidine decarboxylase knockout, HDC−/−) and wild‐type murine AMI models, we demonstrate that histamine deficiency increases the number of microthrombosis after AMI, in accordance with depressed cardiac function. Histamine‐producing myeloid cells, mainly Ly6G+ neutrophils, directly participate in arteriole thrombosis. Histamine deficiency elevates platelet activation and aggregation by enhancing Akt phosphorylation and leads to dysfunctional characteristics in neutrophils which was confirmed by high levels of reactive oxygen species production and CD11b expression. Furthermore, HDC−/− platelets were shown to elicit neutrophil extracellular nucleosomes release, provoke neutrophil‐platelet interactions and promote HDC‐expressing neutrophils recruitment in arteriole thrombosis in vivo. In conclusion, we provide evidence that histamine deficiency promotes coronary microthrombosis and deteriorates cardiac function post‐AMI, which is associated with the enhanced platelets/neutrophils function and neutrophil‐platelet interactions.

Corrigendum: Genetic lesioning of histamine neurons increases sleep-wake fragmentation and reveals their contribution to modafinil-induced wakefulness.

Acute chemogenetic inhibition of histamine (HA) neurons in adult mice induced nonrapid eye movement (NREM) sleep with an increased delta power. By contrast, selective genetic lesioning of HA neurons with caspase in adult mice exhibited a normal sleep-wake cycle overall, except at the diurnal start of the lights-off period, when they remained sleepier. The amount of time spent in NREM sleep and in the wake state in mice with lesioned HA neurons was unchanged over 24 hr, but the sleep-wake cycle was more fragmented. Both the delayed increase in wakefulness at the start of the night and the sleep-wake fragmentation are similar phenotypes to histidine decarboxylase knockout mice, which cannot synthesize HA. Chronic loss of HA neurons did not affect sleep homeostasis after sleep deprivation. However, the chronic loss of HA neurons or chemogenetic inhibition of HA neurons did notably reduce the ability of the wake-promoting compound modafinil to sustain wakefulness. Thus, part of modafinil's wake-promoting actions arise through the HA system.

Genetic lesioning of histamine neurons increases sleep-wake fragmentation and reveals their contribution to modafinil-induced wakefulness.

Acute chemogenetic inhibition of histamine (HA) neurons in adult mice induced nonrapid eye movement (NREM) sleep with an increased delta power. By contrast, selective genetic lesioning of HA neurons with caspase in adult mice exhibited a normal sleep–wake cycle overall, except at the diurnal start of the lights-off period, when they remained sleepier. The amount of time spent in NREM sleep and in the wake state in mice with lesioned HA neurons was unchanged over 24 hr, but the sleep–wake cycle was more fragmented. Both the delayed increase in wakefulness at the start of the night and the sleep–wake fragmentation are similar phenotypes to histidine decarboxylase knockout mice, which cannot synthesize HA. Chronic loss of HA neurons did not affect sleep homeostasis after sleep deprivation. However, the chronic loss of HA neurons or chemogenetic inhibition of HA neurons did notably reduce the ability of the wake-promoting compound modafinil to sustain wakefulness. Thus, part of modafinil’s wake-promoting actions arise through the HA system.

Histamine deficiency aggravates cardiac injury through miR-206/216b-Atg13 axis-mediated autophagic-dependant apoptosis

Histamine is a widely distributed biogenic amine involved in the regulation of an array of biological processes. Serum histamine level is markedly elevated in the early stages of acute myocardial infarction, whereas the role it plays remains unclear. Histidine decarboxylase (HDC) is the unique enzyme responsible for histamine production, and cardiac injury is significantly aggravated in HDC knockout mice (HDC−/−), in which histamine is deficient. We also observed that autophagy was highly activated in cardiomyocytes of HDC−/− mice post acute myocardial infarction (AMI), which was abolished by compensation of exogenous histamine. The in vivo and in vitro results showed that acting through histamine 1 receptor, histamine increased miR-206 and miR-216b, which worked in concert to target to Atg13, resulting in the reduction of autophagy activation under hypoxia and AMI condition. Further study revealed that Atg13 interacted with FADD to promote the activation of caspase-8 and cell apoptosis. Taken together, these data unveil a novel intracellular signaling pathway involved in histamine regulating myocardial autophagy and apoptosis under hypoxia and AMI condition, which might help to more comprehensively evaluate the usage of histamine receptor antagonists and to develop new therapeutic targets for myocardial infarction.

Role of histamine in sepsis-induced organ dysfunction: study using knockout mice of histamine-related genes

Sepsis is the leading cause of death in critically ill patients, and its incidence continues to rise. Sepsis is now defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Histamine assumes a critical role as a major mediator of many pathologic disorders with inflammation and immune reactions. However, direct evidence has not been provided showing the involvement of histamine in the development of multiple organ dysfunction or failure in sepsis. We have found that sepsis-induced major end-organ (lung, liver, and kidney) injury is attenuated in histidine decarboxylase (HDC) gene knockout mice. H1/H2-receptor gene-double knockout mice apparently behave similar to HDC knockout mice in reducing sepsis-related pathologic changes. Here we provide an overview on the role of endogenous histamine as an aggregating mediator that could contribute to the development of major end-organ injury in sepsis.

Induced histamine regulates Ni elution from an implanted Ni wire in mice by downregulating neutrophil migration

Histamine regulates various inflammatory reactions. We have reported that the expression of histidine decarboxylase (HDC) was induced by subcutaneous implantation of nickel (Ni) wire. However, the source and functions of histamine in Ni elution and Ni wire-induced inflammation have not been completely studied. We aimed to elucidate the effects of de novo synthesized histamine on leucocyte infiltration and Ni elution. Implantation of Ni wire induced an increase in the Ni ion content of the surrounding tissues and serum and in the mRNA levels of HDC, a histamine-producing enzyme, macrophage inflammatory protein-2 (MIP-2), a chemoattractant for neutrophils, and monocyte chemoattractant protein-1 (MCP-1), a chemoattractant for monocytes. The Ni wire induced HDC expression even in mast cell-deficient WBB6F1-W/WV mice. In HDC knockout (HDC KO) mice, the Ni wire-induced increase in MIP-2 mRNA expression was significantly higher than that in wild-type mice but not MCP-1. MIP-2 expression was enhanced in histamine H2 receptor knockout (H2R KO) mice but not in WBB6F1-W/WV mice. Histamine inhibited NiCl2 -induced MIP-2 mRNA expression in mouse bone marrow-derived macrophages (BMDMs) obtained from wild-type mice; this inhibition was not observed in BMDMs from H2R KO mice. Ni elution increased in HDC KO mice, in which leucocyte infiltration also increased, and was suppressed in mice treated with neutrophil-specific antibody. These results suggest that the Ni wire induced HDC expression in non-mast cells and that, in the chronic phase of inflammation, endogenous histamine reduced Ni elution, probably through regulation of MIP-2 expression and neutrophil migration.

Histidine Decarboxylase Knockout Mice as a Model of the Pathophysiology of Tourette Syndrome and Related Conditions.

While the normal functions of histamine (HA) in the central nervous system have gradually come into focus over the past 30 years, the relationship of abnormalities in neurotransmitter HA to human disease has been slower to emerge. New insight came with the 2010 description of a rare nonsense mutation in the biosynthetic enzyme histidine decarboxylase (Hdc) that was associated with Tourette syndrome (TS) and related conditions in a single family pedigree. Subsequent genetic work has provided further support for abnormalities of HA signaling in sporadic TS. As a result of this genetic work, Hdc knockout mice, which were generated more than 15 years ago, have been reexamined as a model of the pathophysiology of TS and related conditions. Parallel work in these KO mice and in human carriers of the Hdc mutation has revealed abnormalities in the basal ganglia system and its modulation by dopamine (DA) and has confirmed the etiologic, face, and predictive validity of the model. The Hdc-KO model thus serves as a unique platform to probe the pathophysiology of TS and related conditions, and to generate specific hypotheses for subsequent testing in humans. This chapter summarizes the development and validation of this model and recent and ongoing work using it to further investigate pathophysiological changes that may contribute to these disorders.

Histamine regulation of microglia: Gene-environment interaction in the regulation of central nervous system inflammation

Microglia mediate neuroinflammation and regulate brain development and homeostasis. Microglial abnormalities are implicated in a range of neuropsychiatric pathology, including Tourette syndrome (TS) and autism. Histamine (HA) is both a neurotransmitter and an immune modulator. HA deficiency has been implicated as a rare cause of TS and may contribute to other neuropsychiatric conditions. In vitro studies suggest that HA can regulate microglia, but this has never been explored in vivo. We used immunohistochemistry to examine the effects of HA deficiency in histidine decarboxylase (Hdc) knockout mice and of HA receptor stimulation in wild-type animals. We find HA to regulate microglia in vivo, via the H4 receptor. Chronic HA deficiency in Hdc knockout mice reduces ramifications of microglia in the striatum and (at trend level) in the hypothalamus, but not elsewhere in the brain. Depletion of histaminergic neurons in the hypothalamus has a similar effect. Microglia expressing IGF-1 are particularly reduced, However, the microglial response to challenge with lipopolysacchariade (LPS) is potentiated in Hdc knockout mice. Genetic abnormalities in histaminergic signaling may produce a vulnerability to inflammatory challenge, setting the state for pathogenically dysregulated neuroimmune responses.

Donepezil, an acetylcholine esterase inhibitor, and ABT-239, a histamine H3 receptor antagonist/inverse agonist, require the integrity of brain histamine system to exert biochemical and procognitive effects in the mouse

Histaminergic H3 receptors (H3R) antagonists enhance cognition in preclinical models and modulate neurotransmission, in particular acetylcholine (ACh) release in the cortex and hippocampus, two brain areas involved in memory processing. The cognitive deficits seen in aging and Alzheimer’s disease have been associated with brain cholinergic deficits. Donepezil is one of the acetylcholinesterase (AChE) inhibitor approved for use across the full spectrum of these cognitive disorders. We addressed the question if H3R antagonists and donepezil require an intact histamine neuronal system to exert their procognitive effects. The effect of the H3R antagonist ABT-239 and donepezil were evaluated in the object recognition test (ORT), and on the level of glycogen synthase kinase 3 beta (GSK-3β) phosphorylation in normal and histamine-depleted mice. Systemic administration of ABT-239 or donepezil ameliorated the cognitive performance in the ORT. However, these compounds were ineffective in either genetically (histidine decarboxylase knock-out, HDC-KO) or pharmacologically, by means of intracerebroventricular (i.c.v.) injections of the HDC irreversible inhibitor a-fluoromethylhistidine (a-FMHis), histamine-deficient mice. Western blot analysis revealed that ABT-239 or donepezil systemic treatments increased GSK-3β phosphorylation in cortical and hippocampal homogenates of normal, but not of histamine-depleted mice. Furthermore, administration of the PI3K inhibitor LY294002 that blocks GSK-3β phosphorylation, prevented the procognitive effects of both drugs in normal mice. Our results indicate that both donepezil and ABT-239 require the integrity of the brain histaminergic system to exert their procognitive effects and strongly suggest that impairments of PI3K/AKT/GSK-3β intracellular pathway activation is responsible for the inefficacy of both drugs in histamine-deficient animals.

High-amplitude theta wave bursts characterizing narcoleptic mice and patients are also produced by histamine deficiency in mice.

Histamine and orexins are wake promoters released by hypothalamic neurons. The activity of histamine neurons is increased by orexin neurons. Recently, it has been shown that orexin deficiency entails high-amplitude theta wave bursts during rapid eye movement sleep and cataplexy in narcoleptic mice. The primary aim of this study was to assess whether histamine system is involved in high-amplitude theta wave burst generation during rapid eye movement sleep. The secondary aim was to assess the effects of combined histamine and orexin deficiency on high-amplitude theta wave bursts during rapid eye movement sleep in mice. Twelve histidine-decarboxylase knockout mice with congenital histamine deficiency, seven double mutant mice with combined deficiency of orexin neurons and histamine, and 11 wild-type control mice were studied with electrodes for sleep recordings and a telemetric blood pressure transducer. High-amplitude theta wave bursts during rapid eye movement sleep were detected in each of the histidine-decarboxylase knockout and double mutant mice, whereas only one burst was found in a wild-type control mouse. High-amplitude theta wave bursts occurred significantly more often and were significantly longer in double mutant than in histidine-decarboxylase knockout mice. In conclusion, it was demonstrated that, similarly to orexin, the chronic impairment of histamine entailed high-amplitude theta wave bursts during rapid eye movement sleep. The current data also suggested a synergistic role of orexin and histamine signalling on high-amplitude theta wave bursts during rapid eye movement sleep in mice.

Histamine H3 Receptor Regulates Sensorimotor Gating and Dopaminergic Signaling in the Striatum.

The brain histamine system has been implicated in regulation of sensorimotor gating deficits and in Gilles de la Tourette syndrome. Histamine also regulates alcohol reward and consumption via H3 receptor (H3R), possibly through an interaction with the brain dopaminergic system. Here, we identified the histaminergic mechanism of sensorimotor gating and the role of histamine H3R in the regulation of dopaminergic signaling. We found that H3R knockout mice displayed impaired prepulse inhibition (PPI), indicating deficiency in sensorimotor gating. Histamine H1 receptor knockout and histidine decarboxylase knockout mice had similar PPI as their controls. Dopaminergic drugs increased PPI of H3R knockout mice to the same level as in control mice, suggesting that changes in dopamine receptors might underlie deficient PPI response when H3R is lacking. Striatal dopamine D1 receptor mRNA level was lower, and D1 and D2 receptor-mediated activation of extracellular signal-regulated kinase 1/2 was absent in the striatum of H3R knockout mice, suggesting that H3R is essential for the dopamine receptor-mediated signaling. In conclusion, these findings demonstrate that H3R is an important regulator of sensorimotor gating, and the lack of H3R significantly modifies striatal dopaminergic signaling. These data support the usefulness of H3R ligands in neuropsychiatric disorders with preattentional deficits and disturbances in dopaminergic signaling.

Histamine deficiency exacerbates myocardial injury in acute myocardial infarction through impaired macrophage infiltration and increased cardiomyocyte apoptosis

Histamine is a biogenic amine that is widely distributed and has multiple functions, but the role it plays in acute myocardial infarction (AMI) remains unclear. In this study, we investigated the origin and contribution of endogenous histamine to AMI. Histidine decarboxylase (HDC) is the unique enzyme responsible for histamine generation. Using HDC-EGFP bacterial artificial chromosome (BAC) transgenic mice in which EGFP expression is controlled by the HDC promoter, we identified HDC expression primarily in CD11b+Gr-1+ immature myeloid cells (IMCs) that markedly increase in the early stages of AMI. Deficiency of histamine in HDC knockout mice (HDC−/−) reduced cardiac function and exacerbated the injury of infarcted heart. Furthermore, administering either an H1 receptor antagonist (pyrilamine) or an H2 receptor antagonist (cimetidine) demonstrated a protective effect of histamine against myocardial injury. The results of in vivo and in vitro assays showed that histamine deficiency promotes the apoptosis of cardiomyocytes and inhibits macrophage infiltration. In conclusion, CD11b+Gr-1+ IMCs are the predominant HDC-expressing sites in AMI, and histamine plays a protective role in the process of AMI through inhibition of cardiomyocyte apoptosis and facilitation of macrophage infiltration.

Histidine decarboxylase knockout mice, a genetic model of Tourette syndrome, show repetitive grooming after induced fear

Tics, such as are seen in Tourette syndrome (TS), are common and can cause profound morbidity, but they are poorly understood. Tics are potentiated by psychostimulants, stress, and sleep deprivation. Mutations in the gene histidine decarboxylase (Hdc) have been implicated as a rare genetic cause of TS, and Hdc knockout mice have been validated as a genetic model that recapitulates phenomenological and pathophysiological aspects of the disorder. Tic-like stereotypies in this model have not been observed at baseline but emerge after acute challenge with the psychostimulant d-amphetamine. We tested the ability of an acute stressor to stimulate stereotypies in this model, using tone fear conditioning. Hdc knockout mice acquired conditioned fear normally, as manifested by freezing during the presentation of a tone 48h after it had been paired with a shock. During the 30min following tone presentation, knockout mice showed increased grooming. Heterozygotes exhibited normal freezing and intermediate grooming. These data validate a new paradigm for the examination of tic-like stereotypies in animals without pharmacological challenge and enhance the face validity of the Hdc knockout mouse as a pathophysiologically grounded model of tic disorders.