Histidine decarboxylase deficiency inhibits NBP-induced extramedullary hematopoiesis by modifying bone marrow and spleen microenvironments.

Histidine decarboxylase (HDC), a histamine synthase, is expressed in various hematopoietic cells and is induced by hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF). We previously showed that nitrogen-containing bisphosphonate (NBP)-treatment induces extramedullary hematopoiesis via G-CSF stimulation. However, the function of HDC in NBP-induced medullary and extramedullary hematopoiesis remains unclear. Here, we investigated changes in hematopoiesis in wild-type and HDC-deficient (HDC-KO) mice. NBP treatment did not induce anemia in wild-type or HDC-KO mice, but did produce a gradual increase in serum G-CSF levels in wild-type mice. NBP treatment also enhanced Hdc mRNA expression and erythropoiesis in the spleen and reduced erythropoiesis in bone marrow and the number of vascular adhesion molecule 1 (VCAM-1)-positive macrophages in wild-type mice, as well as increased the levels of hematopoietic progenitor cells and proliferating cells in the spleen and enhanced expression of bone morphogenetic protein 4 (Bmp4), CXC chemokine ligand 12 (Cxcl12), and hypoxia inducible factor 1 (Hif1) in the spleen. However, such changes were not observed in HDC-KO mice. These results suggest that histamine may affect hematopoietic microenvironments of the bone marrow and spleen by changing hematopoiesis-related factors in NBP-induced extramedullary hematopoiesis.

Acute Intestinal Inflammation Depletes/Recruits Histamine-Expressing Myeloid Cells From the Bone Marrow Leading to Exhaustion of MB-HSCs.

BACKGROUND & AIMS: Histidine decarboxylase (HDC), the histamine-synthesizing enzyme, is expressed in a subset of myeloid cells but also marks quiescent myeloid-biased hematopoietic stem cells (MB-HSCs) that are activated upon myeloid demand injury. However, the role of MB-HSCs in dextran sulfate sodium (DSS)-induced acute colitis has not been addressed. METHODS: We investigated HDC+ MB-HSCs and myeloid cells by flow cytometry in acute intestinal inflammation by treating HDC-green fluorescent protein (GFP) male mice with 5% DSS at various time points. HDC+ myeloid cells in the colon also were analyzed by flow cytometry and immunofluorescence staining. Knockout of the HDC gene by using HDC-/-; HDC-GFP and ablation of HDC+ myeloid cells by using HDC-GFP; HDC-tamoxifen-inducible recombinase Cre system; diphtheria toxin receptor (DTR) mice was performed. The role of H2-receptor signaling in acute colitis was addressed by treatment of DSS-treated mice with the H2 agonist dimaprit dihydrochloride. Kaplan-Meier survival analysis was performed to assess the effect on survival. RESULTS: In acute colitis, rapid activation and expansion of MB-HSC from bone marrow was evident early on, followed by a gradual depletion, resulting in profound HSC exhaustion, accompanied by infiltration of the colon by increased HDC+ myeloid cells. Knockout of the HDC gene and ablation of HDC+ myeloid cells enhance the early depletion of HDC+ MB-HSC, and treatment with H2-receptor agonist ameliorates the depletion of MB-HSCs and resulted in significantly increased survival of HDC-GFP mice with acute colitis. CONCLUSIONS: Exhaustion of bone marrow MB-HSCs contributes to the progression of DSS-induced acute colitis, and preservation of quiescence of MB-HSCs by the H2-receptor agonist significantly enhances survival, suggesting the potential for therapeutic utility.

Involvement of histamine in endothelium-dependent relaxation of mesenteric lymphatic vessels.

OBJECTIVES: The knowledge of the basic principles of lymphatic function, still remains, to a large degree, rudimentary and will require significant research efforts. Recent studies of the physiology of the MLVs suggested the presence of an EDRF other than NO. In this study, we tested the hypothesis that lymphatic endothelium-derived histamine relaxes MLVs. METHODS: We measured and analyzed parameters of lymphatic contractility in isolated and pressurized rat MLVs under control conditions and after pharmacological blockade of NO by L-NAME (100 µM) or/and histamine production by α-MHD (10 µM). Effectiveness of α-MHD was confirmed immunohistochemically. We also used immunohistochemical labeling and Western blot analysis of the histamine-producing enzyme, HDC. In addition, we blocked HDC protein expression in MLVs by transient transfection with vivo-morpholino oligos. RESULTS: We found that only combined pharmacological blockade of NO and histamine production completely eliminates flow-dependent relaxation of lymphatic vessels, thus confirming a role for histamine as an EDRF in MLVs. We also confirmed the presence of HDC and histamine inside lymphatic endothelial cells. CONCLUSIONS: This study supports a role for histamine as an EDRF in MLVs.

Histamine modulation of acute nociception involves regulation of Nav 1.8 in primary afferent neurons in mice.

AIMS: To explore the role of histamine in acute pain perception and its possible mechanisms. METHODS: Pain-like behaviors induced by four types of noxious stimuli (hot-plate, tail-pressure, acetic acid, and formalin) were accessed in mice. Nav 1.8 expression and functions in primary afferent neurons were compared between histidine decarboxylase knockout (HDC(-/-) ) mice and their wild-types. RESULTS: HDC(-/-) mice, lacking in endogenous histamine, showed elevated sensitivity to all these noxious stimuli, as compared with the wild-types. In addition, a depletion of endogenous histamine with α-fluoromethylhistidine (α-FMH), a specific HDC inhibitor, or feeding mice a low-histamine diet also enhanced nociception in the wild-types. Nav 1.8 expression in primary afferent neurons was increased both in HDC(-/-) and in α-FMH-treated wild-type mice. A higher Nav 1.8 current density, a lower action potential (AP) threshold, and a higher firing rate in response to suprathreshold stimulation were observed in nociception-related small DRG neurons of HDC(-/-) mice. Nav 1.8 inhibitor A-803467, but not TTX, diminished the hyperexcitability and blocked repetitive AP firing of these neurons. CONCLUSION: Our results indicate that histamine participates in acute pain modulation in a dose-related manner. The regulation of Nav 1.8 expression and the excitability of nociceptive primary afferent neurons may be involved in the underlying mechanisms.

Activation of the central histaminergic system is involved in hypoxia-induced stroke tolerance in adult mice.

We hypothesized that activation of the central histaminergic system is required for neuroprotection induced by hypoxic preconditioning. Wild-type (WT) and histidine decarboxylase knockout (HDC-KO) mice were preconditioned by 3 hours of hypoxia (8% O(2)) and, 48 hours later, subjected to 30 minutes of middle cerebral artery (MCA) occlusion, followed by 24 hours of reperfusion. Hypoxic preconditioning improved neurologic function and decreased infarct volume in WT or HDC-KO mice treated with histamine, but not in HDC-KO or WT mice treated with α-fluoromethylhistidine (α-FMH, an inhibitor of HDC). Laser-Doppler flowmetry analysis showed that hypoxic preconditioning ameliorated cerebral blood flow (CBF) in the periphery of the MCA territory during ischemia in WT mice but not in HDC-KO mice. Histamine decreased in the cortex of WT mice after 2, 3, and 4 hours of hypoxia, and HDC activity increased after 3 hours of hypoxia. Vascular endothelial growth factor (VEGF) mRNA and protein expressions showed a greater increase after hypoxia than those in HDC-KO or α-FMH-treated WT mice. In addition, the VEGF receptor-2 antagonist SU1498 prevented the protective effect of hypoxic preconditioning in infarct volume and reversed increased peripheral CBF in WT mice. Therefore, endogenous histamine is an essential mediator of hypoxic preconditioning. It may function by enhancing hypoxia-induced VEGF expression.

Extramedullary hematopoiesis is dysregulated in histamine-free histidine decarboxylase knockout (HDC-/-) mice.

OBJECTIVE AND DESIGN: In this study we investigated the role of histamine on the extramedullary hematopoiesis. METHODS: Male histidine decarboxylase knockout (HDC(-/-)) mice and wild-type mice were used (n = 5/group). Groups of mice received sublethal total-body gamma irradiation at a single dose of 4 Gy. Spleen cells were studied at different time points post-irradiation by flow cytometry, colony forming unit (CFU) assay, and real-time PCR. For statistical analysis Student's t test, ANOVA, and Holm-Sidak post-hoc test were used. RESULTS: By day 14 after irradiation, spleen cell counts increased almost eightfold in wild-type and not even fourfold in HDC(-/-) mice (P < 0.01). The proliferative capacity and interleukin-3 signaling of stem cells were impaired in HDC(-/-) mice. STAT5 mRNA expression was decreased in granulocyte-myeloid colonies by 72.9 +/- 8.6% (P < 0.001), compared to the wild-type. CONCLUSIONS: The absence of histamine adversely affects splenic hematopoiesis via direct and indirect mechanisms.

Structural features of mammalian histidine decarboxylase reveal the basis for specific inhibition.

For a long time the structural and molecular features of mammalian histidine decarboxylase (EC 4.1.1.22), the enzyme that produces histamine, have evaded characterization. We overcome the experimental problems for the study of this enzyme by using a computer-based modelling and simulation approach, and have now the conditions to use histidine decarboxylase as a target in histamine pharmacology. In this review, we present the recent (last 5 years) advances in the structure-function relationship of histidine decarboxylase and the strategy for the discovery of new drugs.

Enhanced goblet cell hyperplasia in HDC knockout mice with allergic airway inflammation.

BACKGROUND: Histamine is known to have immunoregulatory roles in allergic reactions through histamine receptor 1 (H1R), H2R, H3R and H4R. However, its role in goblet cell hyperplasia in the airways of asthma patients is yet to be clarified. OBJECTIVE: This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine-deficient mice (Hdc-/- mice) with allergic airway inflammation. METHODS: Wild-type and Hdc-/- C57BL/6 mice were sensitized with ovalbumin (OVA). After a 2-week exposure to OVA, goblet cell hyperplasia was evaluated. Cell differentials and cytokines in BALF were analyzed. The mRNA levels of MUC5AC and Gob-5 gene were determined quantitatively. RESULTS: The number of eosinophils in BALF increased in both the sensitized wild-type mice and Hdc-/- mice with OVA inhalation. In addition, the numbers of alveolar macrophages and lymphocytes in BALF increased significantly in the sensitized Hdc-/- mice with OVA inhalation compared to the wild-type mice under the same conditions. The concentrations of Interleukin-4 (IL-4), IL-5, IL-13, Interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and IL-2 in the BALF all increased significantly in both groups compared to those exposed to saline. In particular, the concentration of TNF-alpha in the Hdc-/- mice exposed to OVA was significantly higher than that in the wild-type mice under the same conditions. The mRNA levels of Gob-5 and MUC5AC, and the ratio of the goblet cells in the airway epithelium significantly increased in Hdc-/- mice exposed to OVA compared to wild-type mice. CONCLUSIONS: These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation.

Cutting edge: histamine receptor H4 activation positively regulates in vivo IL-4 and IFN-gamma production by invariant NKT cells.

Histamine (HA) is a biogenic amine with multiple activities in the immune system. In this study we demonstrate that histamine-free histidine decarboxylase-deficient (HDC(-/-)) mice present a numerical and functional deficit in invariant NK T (iNKT) cells as evidenced by a drastic decrease of IL-4 and IFN-gamma production. This deficiency was established both by measuring cytokine levels in the serum and intracellularly among gated iNKT cells. It resulted from the lack of HA, because a single injection of this amine into HDC(-/-) mice sufficed to restore normal IL-4 and IFN-gamma production. HA-induced functional recovery was mediated mainly through the H4 histamine receptor (H4R), as assessed by its abrogation after a single injection of a selective H4R antagonist and the demonstration of a similar iNKT cell deficit in H4R(-/-) mice. Our findings identify a novel function of HA through its H4R and suggest that it might become instrumental in modulating iNKT cell functions.

Progress in allergy signal research on mast cells: the role of histamine in immunological and cardiovascular disease and the transporting system of histamine in the cell.

Since its discovery in 1910, histamine has been regarded as one of the most important biogenic amines in the medical and biological fields. This article summarizes the information about the role of histamine in allergic situations, atherosclerosis, and autoimmune encephalomyelitis, especially focusing on our study with histidine decarboxylase gene knockout mouse. In the allergic bronchial asthma model, histamine positively controls eosinophilia but not bronchial hypersensitivity. Histamine is proved to be an important substance that controls body temperature and respiration in systemic anaphylaxis but its role in controlling blood pressure is minor. Histamine also plays a role in inducing atherosclerosis in the mouse model. We showed that experimental autoimmune encephalomyelitis (EAE) is significantly more severe in histamine-deficient mice with diffuse inflammatory infiltrates in the brain and cerebellum, including a prevalent granulocytic component. Histamine is mainly produced in mast cells and basophils in hematopoietic cells. We've shown that mast cells not only produce histamine, but also uptake it from the environmental medium and release it by allergic stimulants. The protein used for the plasma transport of histamine in basophils was identified as organic cation transporter (OCT3).

Progress in allergy signal research on mast cells: the role of histamine in goblet cell hyperplasia in allergic airway inflammation - a study using the Hdc knockout mouse.

Although histamine is a central mediator in the immediate allergic reaction, its role in goblet cell hyperplasia in the airway of asthma is not completely understood. This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine-deficient mice (Hdc(-/-) mice) with allergic airway inflammation. Wild-type and Hdc(-/-) C57BL/6 mice were sensitized with ovalbumin (OVA). After two-week exposure to OVA, goblet cell hyperplasia was evaluated. Cell differentials in BALF were analyzed. The mRNAs level of MUC5AC and Gob-5 gene were quantitatively determined. The number of eosinophils in BALF increased in both the wild-type mice and Hdc(-/-) mice; however, their ratio in Hdc(-/-) mice was significantly lower than that in the wild-type mice. The mRNA levels of Gob-5 and MUC5AC and the ratio of the goblet cells in the airway epithelium were significantly increased in Hdc(-/-) mice exposed to OVA compared to the wild-type mice under the same condition. These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation.

Histidine decarboxylase (HDC) knock out mouse immune cells have altered expression of ACTH, triiodothyronine and endorphin.

OBJECTIVE: In earlier experiments the immune cells of HDC gene knock-out (HDC-KO) mice contained significantly more serotonin, than those of the wild ones. It was supposed that serotonin, being another biogenic amine, replenishes histamine deficiency. Now we extended our earlier studies to the investigation of the levels of other hormones (adrenocorticotropic hormone [ACTH], beta-endorphin, triiodothyronine [T(3)]) in this knockout model. METHODS: Peritoneal lavage fluid samples and thymuses were gained from HDC-KO and wild type mice. Their cells were prepared for flow cytometry and confocal microscopy by using specific antibodies to the three hormones (1st antibodies) and 2nd antibody to the 1st antibodies. The results of wild type and KO animals were compared. RESULTS: In KO animals the ACTH content in mast cells was significantly reduced and in thymic lymphocytes halved. Endorphin content was reduced both in peritoneal and thymic lymphocytes as well as in mast cells. T(3) content showed a two and a half-fold elevation in the monocyte-macrophage-granulocyte group. The confocal microscopic analysis showed the characteristic picture of HDC-KO mast cells, their cytoplasm being almost free of granules. CONCLUSION: Knock-out of the histidine decarboxylase gene causes a general endocrine imbalance in the hormones which are related to histamine, inside the immune cells. Levels of some hormones are elevated, others decreased.

Elevated CREB activity in embryonic fibroblasts of gene-targeted histamine deficient mice.

OBJECTIVES: Histamine is a known inducer of cAMP-responsive element binding protein (CREB), which plays a key role in initiation of adipogenesis. Our present goal was to study how histamine deficiency impacts CREB signalling and adipogenesis. METHODS: We used a histidine-decarboxylase gene-targeted (HDC KO) mice model lacking endogenous histamine. We measured CREB activity and expression by EMSA, Western blot and real-time RT-PCR, as well as cAMP levels by ELISA in primary embryonic fibroblasts derived from WT and HDC KO mice. The ability of these cells to form adipocytes was also tested in preliminary experiments. RESULTS: We found that in the absence of the histamine, cells show higher constitutive CREB activity and greatly increased intracellular cAMP levels, as well as that in contrast to WT cells, HDC KO fibroblasts are more prone to differentiate into adipocytes. CONCLUSION: These data suggest a newly recognised inhibitory role for histamine in CREB activity and draws attention to the potential role of histamine in adipocyte differentiation.

Highly activated c-fos expression in specific brain regions (ependyma, circumventricular organs, choroid plexus) of histidine decarboxylase deficient mice in response to formalin-induced acute pain.

Activation of different brain regions for acute pain-related stress induced by a single subcutaneous injection of 4% formalin was investigated in histidine decarboxylase-deficient mice. Besides pain- and stress-related brain areas and the tuberomamillary neurons, strong Fos activation and c-fos mRNA expression were found in distinct brain regions and cell types, which have not been activated in wild type control mice. These structures include the circumventricular organs (organum vasculosum of the lamina terminalis, subfornical organ, area postrema), some of the ependymal cells along the wall of the ventricles, tanycytes in the third ventricle's ependyma and the median eminence, as well as in the epithelial cells of the choroid plexus in the lateral, third and fourth ventricles. All of these areas and cell types are known as compartments of the brain-blood-cerebrospinal fluid interface. The present observations provide strong evidence that an acute stressor, formalin-evoked painful stimulus elicits rapid alterations in the activity of neuroglial elements of histidine decarboxylase-deficient mice that are directly involved in the communication between the brain and the cerebrospinal fluid space.

Involvement of chemical mediators in nasal allergic responses of HDC-KO mice.

The present study was undertaken to investigate the involvement of chemical mediators in nasal allergic responses using histidine decarboxylase knockout (HDC-KO) mice. An allergic rhinitis model was developed in HDC-KO and wild-type mice by the intraperitoneal injection of ovalbumin, aluminum hydroxide gel and pertussis toxin. Five days later, they were boosted by a subcutaneous injection of ovalbumin into the back. From day 18 after the first immunization to day 39, intranasal sensitization with ovalbumin was performed every day and the severity of allergic rhinitis was observed by measuring nasal allergic responses and total IgE levels. It was found that the intranasal administration of antigen caused a significant increase of nasal sneezing and rubbing from day 25 to day 39 both in sensitized HDC-KO and wild-type mice. In addition, a significant elevation of total IgE levels in serum was also found both in sensitized HDC-KO and wild-type mice from day 18 to day 39 after the first immunization. L-733,060, a tachykinin NK(1) receptor antagonist at a dose of 10 mg/kg (s.c.), resulted in the dose-dependent inhibition of nasal allergic responses induced by antigen in both HDC-KO and wild-type mice. In addition, both chlorpheniramine at doses of 3 and 10 mg/kg (p.o.) and BW A868C at doses of 0.3 and 1 mg/kg (i.v.) also showed a dose-related reduction of the nasal allergic responses induced by antigen in sensitized wild-type mice. On the other hand, they had no effects on the nasal signs induced by antigen in HDC-KO mice. From these results, it was revealed that substance P induces nasal allergic responses in the mouse model of chronic allergic rhinitis through the activation of tachykinin NK(1) receptors. Therefore, it can be concluded that not only histamine, but also substance P and prostaglandin D(2), participated in the nasal allergic responses induced by antigen in mice.

Lipopolysaccharide promotes and augments metal allergies in mice, dependent on innate immunity and histidine decarboxylase.

BACKGROUND: Few adequate murine models exist for metal allergies, it being especially difficult to induce Ni allergy in mice. OBJECTIVE: We examined the effect of lipopolysaccharide (LPS) on allergies to Ni and other metals in mice. METHODS: Ten days after sensitization with a metal salt and LPS, the ears were challenged with the same metal salt. RESULTS: LPS+NiCl(2) (1 mM) was effective at sensitizing mice to Ni, LPS being effective at very low concentrations whether injected intradermally or intraperitoneally. The ear-swelling response to Ni was more severe and more rapid in C57BL/6 mice than in BALB/c mice. In mast-cell-deficient mice, TNF-alpha-deficient mice, and interestingly even in nude (T cell deficient) mice, NiCl(2)+LPS induced a Ni allergy similar in degree to that in the respective control mice, but it induced Ni allergy only weakly in TLR4-mutant mice, macrophage-depleted mice, and IL-1-deficient mice. The activity of the histamine-forming enzyme histidine decarboxylase (HDC) in the ears increased in parallel with ear swelling, and HDC-deficient mice were resistant to ear swelling. Challenge with NiCl(2)+LPS augmented ear swelling (vs. NiCl(2) alone). LPS induced effective sensitization to other metals (Cr, Co, Pd, or Ag). CONCLUSIONS: These results indicate that in mice, LPS is a very important inducer of metal allergies, and potently promotes them (dependent on both innate immunity and HDC induction in cells other than mast cells). We discussed the idea that the bacterial environment is important for the establishment of metal allergies and for their provocation, and that the current thinking (including the contribution of T cells) should be reappraised in future studies.

Histamine regulates placental cytokine expression--in vivo study on HDC knockout mice.

Successful pregnancy is closely related to polarization toward a Th2 type immune response. As histamine is known to initiate Th2 dominance during inflammatory processes we raised the question whether histamine has any effect on the actual tuning of proper cytokine balance for the proceeding of the gestation. Histamine has multiple functions in the process of pregnancy, different studies have shown the direct and/or indirect presence of histamine action in the placenta as well. As HDC is the unique histamine producing enzyme in eukaryotes, we used HDC (so endogenous histamine)-deficient knockout mice as reliable model for studying histamine-related processes in vivo. We examined the placental histamine content and the expression of histamine receptors and Th1/Th2/Th3 type cytokines in the placenta. We showed for the first time the influence of histamine on the orchestrated regulation of placental cytokine expression. In the absence of local histamine the cytokine balance is shifted toward Th1 types at the maternal-placental interface, threatening pregnancy. We also measured splenic lymphocyte subpopulation ratios in pregnant and non-pregnant mice and found that in pregnancy they are independent of the presence of histamine.

Histamine network in atherosclerosis.

Histamine is a low-molecular-weight amine, synthesized from l-histidine by histidine decarboxylase. It has been suggested that the histamine is produced in the atherosclerotic lesion although the activity of histamine has not been clarified completely. To avoid the pharmacologic problems, genetically engineered mice are useful. We recently observed the histidine decarboxylase-gene knockout mice ameliorates' atherosclerotic region, compared with that of the wild-type control mice. The source of histamine in atherosclerotic lesion should be clarified in details; however, it could be macrophage, endothelial cells, and mast cells. All four types of histamine receptors (H1-H4) have the possibilities to be involved in the atherosclerotic regions. Because H1 and H2 receptors are discovered previously, the activities through those receptors are investigated relatively well, but as the other two types of receptors have been cloned recently, their involvement in atherosclerotic lesion should be investigated further.

The role of histamine in the intracellular survival of Mycobacterium bovis BCG.

The course and outcome of infection with mycobacteria are determined by a complex interplay between the immune system of the host and the survival mechanisms developed by the bacilli. Histamine plays an important role in various processes, including cell division, metabolism, and apoptosis, and it modulates innate and adaptive immune responses. In the present study we investigated the intracellular survival of Mycobacterium bovis BCG in murine bone-marrow macrophages isolated from wild-type (WT) and histidine-decarboxylase knock-out [HDC (-/-)] mice. Mycobacterial titers were significantly higher in the HDC (-/-) macrophages as compared with the WT cells. M. bovis BCG growth in WT macrophages could be enhanced by pyrilamine and cimetidine. Exogenously added histamine decreased the intracellular counts of M. bovis BCG in HDC (-/-) macrophages. Infection of activated macrophages with M. bovis BCG elicited apoptosis, but there was no significant difference between the WT and the HDC (-/-) cells. These bacilli induced comparable levels of tumor necrosis factor-alpha production in the WT and the HDC (-/-) macrophages. M. bovis BCG stimulated interleukin-18 (IL-18) production in the macrophages from WT mice, but not in the HDC (-/-) cells. Exogenously added IL-18 decreased the titers of intracellular mycobacteria in HDC (-/-) cells. In conclusion, these data implicate histamine in the intracellular survival of M. bovis BCG. The cellular control mechanisms restricting the growth of M. bovis BCG are complex and involve H1 and H2 receptor-mediated events. Histamine might be an important mediator of M. bovis BCG-induced IL-18 production, which in turn contributes to immune protection.

Anxiety and cognition in female histidine decarboxylase knockout (Hdc(-/-)) mice.

The role of histamine in brain function has been studied using histidine decarboxylase (HDC) deficient male mice. As the effects of HDC deficiency on brain function might be sex-dependent, we behaviorally analyzed Hdc(-/-) and control female mice. Compared to female control mice, Hdc(-/-) female mice showed hypoactivity, increased measures of anxiety, impairments in water-maze performance, but enhanced passive avoidance memory retention. Following behavioral testing, arginine vasopression (AVP) immunoreactivity was higher in the dorsal hypothalamus and central and basolateral nuclei of the amygdala of Hdc(-/-) than Hdc(+/+) mice. Finally, MAP2 immunoreactivity in the hippocampal CA1 region correlated positively with measures of anxiety in the open-field and light-dark tests and negatively with performance during the hidden sessions of the water-maze. As the effects of HDC deficiency on object recognition, water-maze, and rotorod performance, were sex-dependent, it is important to consider potential effects of sex in the interpretation of the role of histaminergic neurotransmission in brain function.