Bate palmas mutant mice as a model of Kabuki syndrome: Higher susceptibility to infections and vocalization impairments?

The recessive mutant mouse bate palmas (bapa) arose from N-ethyl-N-nitrosourea mutagenesis. Previous studies of our group revealed some behavioral impairments and a mutation in the lysine (K)-specific methyltransferase 2D (Kmt2d) gene. Because mutations in the KMT2D gene in humans are mainly responsible for Kabuki syndrome, this study was proposed to validate bapa mice as a model of Kabuki syndrome. Besides other symptoms, Kabuki syndrome is characterized by increased susceptibility to infections and speech impairments, usually diagnosed in the early childhood. Thus, juvenile male and female bapa mice were studied in different developmental stages (prepubertal period and puberty). To induce sickness behavior and to study infection susceptibility responses, lipopolysaccharide (LPS) was used. To study oral communication, ultrasonic vocalizations were evaluated. Behavioral (open-field test) and central (astrocytic glial fibrillary acidic protein [GFAP] and tyrosine hydroxylase [TH]) evaluations were also performed. Control and bapa female mice emitted 31-kHz ultrasounds on prepubertal period when exploring a novel environment, a frequency not yet described for mice, being defined as 31-kHz exploratory vocalizations. Males, LPS, and puberty inhibited these vocalizations. Bapa mice presented increased motor/exploratory behaviors on prepubertal period due to increased striatal TH expression, revealing striatal dopaminergic system hyperactivity. Combining open-field behavior and GFAP expression, bapa mice did not develop LPS tolerance, that is, they remained expressing signs of sickness behavior after LPS challenge, being more susceptible to infectious/inflammatory processes. It was concluded that bapa mice is a robust experimental model of Kabuki syndrome.

Billings reservoir water used for human consumption presents microbiological contaminants and induces both behavior impairments and astrogliosis in zebrafish.

The Billings reservoir is the largest water-storage facility in the São Paulo Metropolitan Region, with only a small part of the reservoir used for water supply. Recently, the São Paulo Metropolitan Region has experienced the greatest water collapse ever recorded. Thus, the intensification of use of the Billings reservoir should be considered. The objective of this study was to evaluate the quality of the water from different areas of the Billings reservoir related to human consumption (water supply and fishing): Rio Pequeno, Rio Grande, and Bororé rivers. We performed microbiological and physical studies on one water sample collected at each of these sites. Adult zebrafish were exposed to such water samples and their behaviors were evaluated. Finally, we studied central glial fibrillary acidic protein (GFAP) expression, which is related to neuroinflammatory processes. Water samples from Rio Pequeno, Rio Grande, and Bororé presented microbiological contamination for Escherichia coli and heterotrophic bacteria. Water from the Rio Pequeno river induced both motor/exploratory impairments and anxiogenic-like behavior in zebrafish. Water from the Bororé river induced behaviors in zebrafish related to respiratory impairments (hypoxia) as well as higher alarm reaction. Zebrafish exposed to water from the Bororé also presented astrogliosis, which seems to have happened in detrimental of the high heterotrophic bacterial contamination. Rio Grande and Bororé water increased the lethality rates. Considering the present results of microbiological contaminants and behavior impairments, lethality, as well as astrogliosis in zebrafish, the water from Rio Pequeno, Rio Grande, and Bororé rivers should be considered unacceptable for human use in their untreated state. The Basic Sanitation Company of the State of Sao Paulo should consider adopting rigorous processes of microbiological water treatment. Authorization for fishing at Bororé river should be reconsidered.

First chemical evaluation and toxicity of Casinga-cheirosa to Balb-c male mice.

Laetia suaveolens, known as "casinga-cheirosa", crude extract EB719 has previously shown cytotoxic activity against prostate cancer and squamous cell carcinoma. For the first time, seven molecules were isolated from its apolar-α-tocopherol (1) and sitosterol (2)-and polar-3-O-caffeoylquinic acid (3), 4-O-caffeoylquinic acid (4), 5-O-feruloylquinic acid (5), hyperoside (6), and isoquercitrin (7)-fractions. Acute toxicity was determined in a two-stage experiment: (1) a reduced number of Balb-c male mice received 5000 mg/kg of EB719 to allow evaluation of general activity and other 27 parameters, plus death, up to the establishment of non-lethal dose (NLD), as well as lethal dose 50% (LD50); (2) NLD was administered and diazepam introduced as reference drug. EB719 showed LD50=178.0 mg/kg, and NLD 156.3 mg/kg. In stage one EB719 did not influence general activity, but provoked impairment in grasp reflexes, tail squeeze and breathing; piloerection and cyanosis were increased. In stage two, alterations occurred in auricular reflex, piloerection and breathing after diazepam administration, but not in response to EB719. Intestinal hemorrhage caused by local bleeding was observed after necropsy, and may be the main cause of animals' death other than a systemic effect of the extract. Although the isolated compounds are biologically and pharmacologically active in both men and animal systems, it is premature to relate their occurrence in EB719 to the observed intestine hemorrhage in mice.

Ivermectin prevents stress-induced testicular damage in juvenile rats.

Ivermectin is a popular antiparasitic drug used in veterinary and human medicine. Studies by our group have shown that therapeutic doses of ivermectin induce some brain and behavioral impairments, especially in the reproductive sphere. So far, the studies were focused in adulthood. Considering that juveniles are more susceptible to drugs during developmental stages and both farm/domestic animals and humans have been medicated with ivermectin in youth, it is necessary to evaluate the possible harm effects in youth. The stress variable is also important, as it potentially influences the effects produced by ivermectin. Therefore, the objective of this study was to evaluate morphofunctional and hormonal reproductive aspects of juvenile rats exposed to ivermectin and/or stressed. Prepubertal male rats were treated with 0.2 or 1.0 mg/kg of ivermectin (a therapeutic dose and a higher dose, respectively). Rats were also submitted to a restraint stress session. The testis morphology and histology were analyzed and plasma testosterone levels were measured. The two doses of ivermectin did not induce a biologically relevant effect on testis and testosterone levels of rats. However, restraint stress impaired macroscopic and microscopic morphometric and stereological parameters, as well as the histology of the testis: it increased the relative testis weight, the tubular diameter, the tubular luminal diameter, and the tubular cellular index, and injured the interstitial area. Previous treatment of juvenile rats with ivermectin prevented most of the stress-induced testes injuries. In conclusion, in addition to be a remarkable antiparasitic agent, ivermectin prevented stress-induced testes injuries in juvenile rats.

Does a therapeutical dose of ivermectin impairs testicular homeostasis of rats via excessive apoptosis?

Ivermectin is a medication used to treat parasite infestations in humans and in veterinary medicine. Previously we showed that therapeutical doses of ivermectin impaired spermatogenesis and spermiogenesis in adult rats. The present study was proposed to understand the pathophysiological mechanism that triggered these impairments induced by ivermectin. It was a particular objective to study if ivermectin induced excessive apoptosis. Adult rats were treated with a therapeutical dose of ivermectin (subcutaneously). Their testis was evaluated for the expression of caspase-3 (a marker of apoptosis), using immunohistochemistry techniques. Results revealed that ivermectin treatment increased the expression of caspase-3 (labeled seminiferous tubules and strongly labeled tubules), as well as increased the number of tubules that presented labeled cells in the tubular lumen, compared to the data of the control group. In conclusion, a therapeutical dose of ivermectin induced expressive apoptosis in cells of the seminiferous tubules of rats, affecting the testicular natural homeostasis process, which resulted in the spermatogenesis and spermiogenesis impairments previously reported.

Maternal treatment with picrotoxin in late pregnancy improved female sexual behavior but did not alter male sexual behavior of offspring.

Previous studies from our laboratory investigated the effects of picrotoxin (PT), a γ-aminobutyric acid receptor antagonist administered during several perinatal periods, on the sexual behavior of male and female rats. We observed that the time of perinatal exposure to PT is critical to determine either facilitation or impairment of sexual behavior. The present study evaluated the effects of prenatal administration of a single dose of PT on gestation day 18 of dams (the first critical period of male brain sexual differentiation) on sexual behavior of male and female offspring. Thus, female Wistar rats were mated with males and, on gestation day 18, received 0.6 mg/kg of PT or 0.9% saline solution subcutaneously. On postnatal day 1, the offspring were weighed and several measures of sexual development were assessed. The sexual behaviors and the general activity in the open field of adult male and ovariectomized, hormone-treated female rats were observed. On comparison with the control group, maternal PT treatment: (i) did not alter the maternal weight, pup weight, anogenital distance, or male and female general activity; (ii) increased female sexual behavior, that is, decreased the latencies to first mount, first lordosis, and tenth lordosis, and the percentage of females presenting lordosis; and (iii) did not alter male sexual behavior. It is suggested that prenatal PT exposure interfered with epigenetic mechanisms related to the development of sex differences in the brain, leading to the observed sexually dimorphic effects on sexual behavior.

Progressive tremor and motor impairment in seizure-prone mutant tremor mice are associated with neurotransmitter dysfunction.

BACKGROUND: The tremor mutant mice present motor impairments comprised of whole-body tremors, ataxia, decreased exploratory behavior, and audiogenic seizures. OBJECTIVES: This study aims to investigate the development of motor dysfunction in this mutant mouse and the relationships with cortical, striatal, and cerebellar levels of GABA, glutamate, glycine, dopamine (DA), serotonin (5-HT), noradrenaline (NOR), and its metabolites. The serum cytokines levels, myelin content, and the astrocytic expression of the glial fibrillary acidic protein (GFAP) investigated the possible influence of inflammation in motor dysfunction. RESULTS: Relative to wild-type (WT) mice, the tremor mice presented: increased tremors and bradykinesia associated with postural instability, decreased range of motion, and difficulty in initiating voluntary movements directly proportional to age; reduced step length for right and left hindlimbs; reduced cortical GABA, glutamate and, aspartate levels, the DOPAC/DA and ratio and increased the NOR levels; in the striatum, the levels of glycine and aspartate were reduced while the HVA levels, the HVA/DA and 5HIAA/5-HT ratios increased; in the cerebellum the glycine, NOR and 5-HIAA levels increased. CONCLUSIONS: We suggest that the motor disturbances resulted mainly from the activation of the indirect striatal inhibitory pathway to the frontal cortex mediated by GABA, glutamate, and aspartate, reducing the dopaminergic activity at the prefrontal cortex, which was associated with the progressive tremor. The reduced striatal and increased cerebellar glycine levels could be partially responsible for the mutant tremor motor disturbances.

Hypoactivity of the central dopaminergic system and autistic-like behavior induced by a single early prenatal exposure to lipopolysaccharide.

The aim of the present study was to evaluate the behavioral patterns associated with autism and the prevalence of these behaviors in males and females, to verify whether our model of lipopolysaccharide (LPS) administration represents an experimental model of autism. For this, we prenatally exposed Wistar rats to LPS (100 µg/kg, intraperitoneally, on gestational day 9.5), which mimics infection by gram-negative bacteria. Furthermore, because the exact mechanisms by which autism develops are still unknown, we investigated the neurological mechanisms that might underlie the behavioral alterations that were observed. Because we previously had demonstrated that prenatal LPS decreases striatal dopamine (DA) and metabolite levels, the striatal dopaminergic system (tyrosine hydroxylase [TH] and DA receptors D1a and D2) and glial cells (astrocytes and microglia) were analyzed by using immunohistochemistry, immunoblotting, and real-time PCR. Our results show that prenatal LPS exposure impaired communication (ultrasonic vocalizations) in male pups and learning and memory (T-maze spontaneous alternation) in male adults, as well as inducing repetitive/restricted behavior, but did not change social interactions in either infancy (play behavior) or adulthood in females. Moreover, although the expression of DA receptors was unchanged, the experimental animals exhibited reduced striatal TH levels, indicating that reduced DA synthesis impaired the striatal dopaminergic system. The expression of glial cell markers was not increased, which suggests that prenatal LPS did not induce permanent neuroinflammation in the striatum. Together with our previous finding of social impairments in males, the present findings demonstrate that prenatal LPS induced autism-like effects and also a hypoactivation of the dopaminergic system.

Maternal exposure to picrotoxin modifies the response of the GABAA receptor during sexual behavior of adult male rat offspring.

This study investigated whether perinatal exposure to picrotoxin, a GABAA antagonist, modifies the effect of muscimol, a GABAA agonist, on the sexual behavior of adult male rats. Two hours after birth and then once daily during the next 9 days of lactation, dams received picrotoxin (0.75 mg/kg subcutaneously) or saline (1 ml/kg subcutaneously). The adult male offspring from the picrotoxin and saline groups received saline (1 ml/kg intraperitoneally) or muscimol (1 mg/kg intraperitoneally), and 15 min later, their sexual behavior was assessed. Muscimol treatment in the saline-exposed group increased the mount and intromission latencies. However, these effects were absent in the picrotoxin-exposed groups. The latencies to first ejaculation, postejaculatory mount, and intromission were decreased in both picrotoxin-exposed groups relative to the saline-exposed groups. The picrotoxin+muscimol-treated rats required more intromissions to ejaculate and the picrotoxin-exposed groups made more ejaculations than the saline-exposed groups. Thus, muscimol treatment did not increase the mount and intromission latencies following picrotoxin exposure, but increased the ejaculation frequency, which did not differ between the picrotoxin+muscimol and the picrotoxin+saline groups. These data indicate that perinatal picrotoxin treatment interfered with GABAA receptor development.

Mouse Behavior in the Open-field Test after Meloxicam Administration.

Several analgesics are suggested for pain management in mice. Nonsteroidal antiinflammatories (NSAIDs), such as meloxicam can be administered for the treatment of inflammation and acute pain; however, several side effects can occur which include gastrointestinal ulceration and renal and hepatic toxicity. We previously performed a pilot study to test the antinociceptive activity of meloxicam in mice, but we observed behavioral changes in unoperated control mice. These observations spurred further investigation. One hypothesis for the result was potential differences in formulation between commercial brands of meloxicam. Thus, this current study aimed to evaluate the effects of 3 different commercial brands of meloxicam (20 mg/kg) in the general activity of mice using the open field test. Our results showed that meloxicam had several effects on mouse behavior and caused the formation of skin lesions at the injection site, depending on the brand of the drug. The most significant adverse effect observed was decreased exploratory activity. Grooming frequency was reduced in all groups. These adverse effects might be related to the quality of the drugs because meloxicam formulations can contain crystal polymorphisms that affect drug quality and efficacy. This study points out the importance of drug quality variation that can affect the outcome of behavioral studies in mice.

Long-term obesity is associated with depression and neuroinflammation.

OBJECTIVE: Obesity is characterized by a state of chronic, low-intensity systemic inflammation frequently associated with insulin resistance and dyslipidemia. METHODS: Given that chronic inflammation has been implicated in the pathogenesis of mood disorders, we investigated if chronic obesity that was initiated early in life - lasting through adulthood - could be more harmful to memory impairment and mood fluctuations such as depression. RESULTS: Here we show that pre-pubertal male rats (30 days old) treated with a high-fat diet (40%) for 8-months gained ~50% more weight when compared to controls, exhibited depression and anxiety-like behaviors but no memory impairment. The prefrontal cortex of the obese rats exhibited an increase in the expression of genes related to inflammatory response, such as NFKb, MMP9, CCl2, PPARb, and PPARg. There were no alterations in genes known to be related to depression. CONCLUSION: Long-lasting obesity with onset in prepuberal age led to depression and neuroinflammation but not to memory impairment.

Vertical exposition to Luffa operculata extract deregulates behavior and hypothalamus neurotransmitters in juvenile rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Luffa operculata (L.) Cogn (Cucurbitaceae) is a traditional plant popularly used in the abortion induction, against sinusitis and is toxic. AIM OF THE STUDY: To verify the influence of the aqueous extract obtained from the dry fruit of L. operculata (BNE) on the male rats vertically exposed to a subabortive dose of BNE, by evaluating alterations in behavior and neurochemical features in hypothalamus, striatum and frontal cortex, at a juvenile age, after receiving a stress challenge given by the use of the "New York subway stress" technique (NYS). MATERIALS AND METHODS: Pregnant female rats (F0 generation) received 1.0 mg/kg BNE, or distilled water (100 mL/kg), by gavage, between gestation days GD17 and GD21. The pups were weaned at PND21 and were kept up to PND60 (juvenile age) in controlled environmental conditions. Four groups were obtained: control (CG), experimental (EG), stress control (SCG) and stress experimental (SEG) After being stressed, the animals were behavioral screened for in the open field (OF) and in light-dark box (LDB) apparatuses. They were euthanized, and the liver, kidneys and brain were removed for both macroscopic and microscopic analyses, and for quantification of vanillylmandelic acid (VMA), norepinephrine (NE), dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and the serotonin (5-HT) and its metabolite 5-hydroxyindolylacetic acid (5-HIAA) were accessed in the hypothalamus, frontal cortex and striatum. RESULTS AND DISCUSSION: although most of the behavior changes were due to the stress challenge, the rats spent more time in the dark side of the LDB and were less likely to explore the light side, indicating that the treatment with BNE induced to fear. Interferences of BNE over behavior were due to impairment of VMA, NE, 5-HT and DA and increasing of DOPAC in the hypothalamus, and an increase of 5-HIAA in the frontal cortex, indicating alterations in the hypothalamic-hypophysis-adrenal axis (HHAA). No macroscopic or histopathological changes were observed in the liver, kidneys, or brain, although GFAP was diminished in the SCG, as expected for stressed rats. CONCLUSION: the vertical exposition of juvenile rats to BNE led to the manifestation of fear and to a down regulation of the hypothalamic-hypophysis-adrenal axis.

Luffa operculata at a late period of gestation dysregulates melatonin and cytokines interfering with weight of dams and their male offspring.

ETHNOPHARMACOLOGICAL RELEVANCE: The tea made with the fruits of Luffa operculata (L.) Cogn. (Cucurbitaceae; EBN) is popularly used as abortive. AIM OF THE STUDY: The present work aimed at accessing how the exposition of female Wistar rats to 1.0 mg/kg of EBN (experimental group, EG), or distilled water (control group, CG), by gavage, at gestational days (GD) 17-21 interfered with the reproductive performance, and with dams' behavior after weaning. MATERIALS AND METHODS: At post-natal day 2 (PND2), the number of male and female pups was evaluated, as well as their weight. After weaning (PND21), dams were euthanized, and their liver and kidneys were removed for histological and biochemical analyses, while the blood was used in the evaluation of cytokines IL-1α, IL-1ß, IL-6 and TNF-α, corticosterone, adrenocorticotrophic hormone, melatonin, AST, ALT and creatinine levels. RESULTS AND DISCUSSION: Dams that were treated with EBN showed an anxiety-like behavior, weight loss at the end of gestation and weight gain at weaning, accompanied with a significant decrease in pro-inflammatory cytokines and in the melatonin level. No significant histological or biochemical alterations have occurred in the liver or kidneys. The number of female pups was significantly higher in the EG. The male pups showed weight gain at PND60. CONCLUSION: The presence of cucurbitacins is probably involved in the dysregulations that were found, due to their polycyclic steroid triterpene structure.

Prenatal lipopolysaccharide reduces social behavior in male offspring.

OBJECTIVE: This study investigated the relationship between maternal sickness behavior during pregnancy and offspring development and behavior. METHODS: Pregnant Wistar rats were administered with lipopolysaccharide (LPS, 100 microg/kg, i.p.) on gestation day (GD) 9.5. Dams' sickness behavior was analyzed, and at birth, offspring number and weight were evaluated. Male offspring was evaluated through physical development, play behavior, adult social interaction, plus maze studies and morphological analysis of the brain. RESULTS: Results, with respect to the control group, showed that: (1) LPS decreased general activity, food intake, and weight gain in dams, but no pyrexia was observed following treatment; (2) LPS reduced litter size, but no alterations in physical development were observed; (3) LPS reduced play behavior parameters in baby rats; (4) LPS decreased adult social interaction; (5) no alterations were observed between groups on plus maze studies; (6) no differences were observed between groups on morphological analyses of the brain. CONCLUSION: These data reveal that LPS administered on GD 9.5 impaired male offspring's social behavior in infancy and adulthood. These results may be related to an alteration in motivational states or/and increased anxiety.

Prenatal lipopolysaccharide exposure affects maternal behavior and male offspring sexual behavior in adulthood.

OBJECTIVE: This study investigates the effects of prenatal lipopolysaccharide (LPS) exposure on the maternal behavior of pregnant rats and the physical development and sexual behavior of their male offspring in adulthood. METHODS: For two experiments, pregnant rats were injected with LPS (250 microg/kg, i.p.) on gestation day (GD) 21. In the first experiment, the maternal behavior (postnatal day, PND, 6) and the dam's open-field general activity (PND7) were evaluated. In the second experiment, the maternal pre- and postnatal parameters, the pup's development, the offspring's sexual behavior in adulthood, and the pup's organ weights were assessed. RESULTS: Compared to the control group, the LPS-treated dams presented reduced maternal behavior, decreased general activity, a smaller body weight difference between GD21 and PND1, a greater number of perinatal deaths, and smaller litters. For the male pups, LPS treatment resulted in a decreased body weight on PND2, whereas the anogenital distance and the day of testis descent were not modified. The male sexual behavior was impaired by prenatal LPS. Particularly the number of ejaculating animals was reduced. The testis weight was also lower in the prenatally LPS-treated rats than in the control rats. CONCLUSION: We propose that prenatal LPS exposure on GD21 acts as an imprinting factor that interferes with the programming of brain sexual determination in offspring.

A Simple and Fast Battery Test for Phenotypic Characterization of Mice.

Despite the great number of test batteries already known to assess the behavior of genetically modified and inbred strains of mice, only a few of them focus on basic neurological parameters. The purpose of the battery test proposed is to settle a specific methodology to characterize the phenotype of neurological disease models in mutant or genetically modified mice. This methodology is simple and efficient in order to analyze several parameters, including general activity, sensory nervous system, sensorimotor system, central nervous system and autonomous nervous system. This can aid the choice of specific additional tests as well as the determination of an interrelationship among phenotypic alterations observed. Although being efficient for a first analysis of a mouse model, interpretation of the results must be carefully made because phenotype manifestation may vary due to many parameters, including mouse strain, environmental and housing condition, animal-experimenter interaction, sample size and tests order. It is important to consider as a critical point if handling procedures are aversive. The results acquired with the analysis of 18 parameters together provide preliminary data to characterize mouse phenotype and helps selecting more specific tests.

Pioglitazone abolishes cognition impairments as well as BDNF and neurotensin disturbances in a rat model of autism.

We have shown that exposure of rats to lipopolysaccharide (LPS) during gestation induces autistic-like behaviors in juvenile offspring and pioglitazone post treatment corrects social and communication deficits. The first objective of the present study was to evaluate the cognition of the rats, because this is also a behavioral sphere committed in autism. Second, biomarkers related to pioglitazone pathways and autism were studied to try to understand their mechanisms. We used our rat model of autism and pioglitazone was administered daily to these young offspring. T-maze spontaneous alternations tests, plasma levels of brain-derived neurotrophic factor (BDNF), beta-endorphin, neurotensin, oxytocin, and substance P were all studied. Exposure of rats to LPS during gestation induced cognitive deficits in the young offspring, elevated BDNF levels and decreased neurotensin levels. Daily postnatal pioglitazone treatment abolished cognition impairments as well as BDNF and neurotensin disturbances. Together with our previous studies, we suggest pioglitazone as a candidate for the treatment of autism, because it improved the responses of the three most typical autistic-like behaviors. BDNF and neurotensin also appeared to be related to the autistic-like behaviors and should be considered for therapeutic purposes.

LPS-induced sickness behavior is not affected by selenium but is switched off by psychogenic stress in rats.

Sickness behavior (SB) is considered part of the adaptive behavioral and neuroimmune changes that occur in response to inflammatory processes. However, SB is a motivational state modulated by the environmental context. The objective of this study was to evaluate if selenium could ameliorate symptoms of SB and if stress would affect these responses. We induced SB in rats using lipopolysaccharide (LPS). We choose selenium based on our findings of LPS-exposure decreasing selenium levels in rats. We exposed these rats to a psychogenic stress and studied motivational modulation paradigms, such as cure of the organism, preservation of the species, and fight or flight. We studied ultrasonic vocalizations, open-field behaviors, body weight, and IL-1 beta and IFN-gamma serum levels. LPS-induced SB was evidenced by decreased motor/exploratory activity and increased proinflammatory mediators' levels. Selenium treatment did not exert beneficial effects on SB, revealing that probably the selenium deficiency was not related to SB. When analyzed with the stress paradigm, the behavior of rats was differentially affected. LPS did not affect behavior in the presence of stress. SB was abrogated during stressor events to prioritize survival behaviors, such as fight-or-flight. Contrarily, the association of LPS, selenium, and stress induced SB even during stressor events, revealing that this combination induced a cumulative toxic effect.

Therapeutical doses of ivermectin and its association with stress disrupt motor and social behaviors of juvenile rats and serotonergic and dopaminergic systems.

Ivermectin is a human and veterinary antiparasitic drug which is one of the most widely used in the world. Studies from our group have revealed several behavioral and neurochemical impairments induced by therapeutic doses of ivermectin in adult rats. However, the effects on juveniles remain unknown. Ivermectin has been prescribed for juvenile humans, pets and farm animals, which still show remarkable development and postnatal maturation and may be more susceptible to drug interventions. Hence, we studied the behavioral and neurochemical effects of two therapeutical doses (0.2 and 1.0 mg/kg) of ivermectin in juvenile rats. As it is underestimated in prescriptions, the stress factor was also studied. Ivermectin 1.0 mg/kg induced hyperlocomotion in juvenile rats. Association of 1.0 mg/kg ivermectin with stress induced hypolocomotion in rats. Ivermectin 1.0 mg/kg whether or not associated with stress exacerbated socialization of rats. Ivermectin did not induce anxiety-like behavior neither affected corticosterone levels of juvenile rats. The motor/exploratory behavioral findings induced by association of ivermectin and stress seem to be triggered after the increase in the striatal serotonergic system activity. Association of ivermectin with stress increased striatal dopamine levels, which increased (excessive) social play behavior. Our results suggest a review of the prescribed dose of ivermectin for juvenile humans and pets. Moreover, the stress factor should be considered for ivermectin medical prescriptions, since it may exacerbate behavioral and neurochemical disturbances.

Genetic and behavioral characterization of a Kmt2d mouse mutant, a new model for Kabuki Syndrome.

The recessive mutant mice bate palmas (bapa) - claps in Portuguese arose from N-ethyl-N-nitrosourea mutagenesis. A single nucleotide, T > C, change in exon 13, leading to a Thr1289 Ala substitution, was identified in the lysine (K)-specific methyltransferase 2D gene (Kmt2d) located on chromosome 15. Mutations with a loss-of-function in the KMT2D gene on chromosome 12 in humans are responsible for Kabuki syndrome (KS). Phenotypic characterization of the bapa mutant was performed using a behavioral test battery to evaluate the parameters related to general activity, the sensory nervous system, the psychomotor system, and the autonomous nervous system, as well as to measure motor function and spatial memory. Relative to BALB/cJ mice, the bapa mutant showed sensory and psychomotor impairments, such as hypotonia denoted by a surface righting reflex impairment and hindquarter fall, and a reduction in the auricular reflex, suggesting hearing impairment. Additionally, the enhanced general activity showed by the increased rearing and grooming frequency, distance traveled and average speed possibly presupposes the presence of hyperactivity of bapa mice compared with the control group. A slight motor coordination dysfunction was showed in bapa mice, which had a longer crossing time on the balance beam compared with BALB/cJ controls. Male bapa mice also showed spatial gait pattern changes, such as a shorter stride length and shorter step length. In conclusion, the bapa mouse may be a valuable animal model to study the mechanisms involved in psychomotor and behavior impairments, such as hypotonia, fine motor coordination and hyperactivity linked to the Kmt2d mutation.