The role of PTEN signaling in synaptic function: Implications in autism spectrum disorder.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) regulates several cellular processes including survival, proliferation, and metabolism. In the brain, PTEN is a key modulator of synaptic function, and is involved in regulating synaptogenesis, connectivity, and synaptic plasticity. Herein we discuss how alterations in PTEN can disturb these mechanisms, thus compromising normal synaptic function and consequently contributing to behavioral and cognitive phenotypes observed in autism spectrum disorder (ASD). As the role of PTEN in synaptic function is linked to ASD, a deeper understanding of this interaction will shed light on the pathological mechanisms involved in ASD, contributing to the development of new therapies.

Inverse Control of Turning Behavior by Dopamine D1 Receptor Signaling in Columnar and Ring Neurons of the Central Complex in Drosophila.

Action selection is a prerequisite for decision-making and a fundamental aspect to any goal-directed locomotion; it requires integration of sensory signals and internal states to translate them into action sequences. Here, we introduce a novel behavioral analysis to study neural circuits and mechanisms underlying action selection and decision-making in freely moving Drosophila. We discovered preferred patterns of motor activity and turning behavior. These patterns are impaired in FoxP mutant flies, which present an altered temporal organization of motor actions and turning behavior, reminiscent of indecisiveness. Then, focusing on central complex (CX) circuits known to integrate different sensory modalities and controlling premotor regions, we show that action sequences and turning behavior are regulated by dopamine D1-like receptor (Dop1R1) signaling. Dop1R1 inputs onto CX columnar ellipsoid body-protocerebral bridge gall (E-PG) neuron and ellipsoid body (EB) R2/R4m ring neuron circuits both negatively gate motor activity but inversely control turning behavior. Although flies deficient of D1 receptor signaling present normal turning behavior despite decreased activity, restoring Dop1R1 level in R2/R4m-specific circuitry affects the temporal organization of motor actions and turning. We finally show EB R2/R4m neurons are in contact with E-PG neurons that are thought to encode body orientation and heading direction of the fly. These findings suggest that Dop1R1 signaling in E-PG and EB R2/4 m circuits are compared against each other, thereby modulating patterns of activity and turning behavior for goal-directed locomotion.

Lifespan Extension Induced by Caffeine in Caenorhabditis elegans is Partially Dependent on Adenosine Signaling.

Caffeine is a widely used psychoactive substance. Studies have shown that caffeine may play a protective role in aging-associated disorders. However, the mechanisms by which caffeine modulates aging are not yet clear. In this study, we have shown that caffeine increases Caenorhabditis elegans lifespan, delays its larval development, reduces reproduction and body length. These phenotypes were partly reversed by worm's exposure to adenosine, which suggest a putative common target. Moreover, they were dependent on a functional insulin/IGF-1-like pathway. Our results may shed light on new genetic determinants of aging.

Dopamine signaling regulates fat content through ß-oxidation in Caenorhabditis elegans.

The regulation of energy balance involves an intricate interplay between neural mechanisms that respond to internal and external cues of energy demand and food availability. Compelling data have implicated the neurotransmitter dopamine as an important part of body weight regulation. However, the precise mechanisms through which dopamine regulates energy homeostasis remain poorly understood. Here, we investigate mechanisms through which dopamine modulates energy storage. We showed that dopamine signaling regulates fat reservoirs in Caenorhabditis elegans. We found that the fat reducing effects of dopamine were dependent on dopaminergic receptors and a set of fat oxidation enzymes. Our findings reveal an ancient role for dopaminergic regulation of fat and suggest that dopamine signaling elicits this outcome through cascades that ultimately mobilize peripheral fat depots.

Behavioral and metabolic effects of the atypical antipsychotic ziprasidone on the nematode Caenorhabditis elegans.

Atypical antipsychotics are associated with metabolic syndrome, primarily associated with weight gain. The effects of Ziprasidone, an atypical antipsychotic, on metabolic syndrome has yet to be evaluated. Here in, we evaluated lipid accumulation and behavioral changes in a new experimental model, the nematode Caenorhabditis elegans (C. elegans). Behavioral parameters in the worms were evaluated 24 h after Ziprasidone treatment. Subsequently, lipid accumulation was examined using Nile red, LipidTox green and BODIPY labeling. Ziprasidone at 40 µM for 24 h effectively decreased the fluorescence labeling of all markers in intestinal cells of C. elegans compared to control (0.16% dimethyl sulfoxide). Ziprasidone did not alter behaviors related to energetic balance, such as pharynx pumping, defecation cycles and movement. There was, however, a reduction in egg-production, egg-laying and body-length in nematodes exposed to Ziprasidone without any changes in the progression of larval stages. The serotoninergic pathway did not appear to modulate Ziprasidone's effects on Nile red fluorescence. Additionally, Ziprasidone did not alter lipid accumulation in daf-16 or crh-1 deletion mutants (orthologous of the transcription factors DAF-16 and CREB, respectively). These results suggest that Ziprasidone alters reproductive behavior, morphology and lipid reserves in the intestinal cells of C. elegans. Our results highlight that the DAF-16 and CREB transcription factors are essential for Ziprasidone-induced fat store reduction.

Cooperation of non-effective concentration of glutamatergic system modulators and antioxidant against oxidative stress induced by quinolinic acid.

Excessive formation of reactive oxygen species (ROS) and disruption of glutamate uptake have been hypothesized as key mechanisms contributing to quinolinic acid (QA)-induced toxicity. Thus, here we investigate if the use of diphenyl diselenide (PhSe)(2), guanosine (GUO) and MK-801, alone or in combination, could protect rat brain slices from QA-induced toxicity. QA (1 mM) increased ROS formation, thiobarbituric acid reactive substances (TBARS) and decreased cell viability after 2 h of exposure. (PhSe)(2) (1 µM) protected against this ROS formation in the cortex and the striatum and also prevented decreases in cell viability induced by QA. (PhSe)(2) (5 µM) prevented ROS formation in the hippocampus. GUO (10 and 100 µM) blocked the increase in ROS formation caused by QA and MK-801 (20 and 100 µM) abolished the pro-oxidant effect of QA. When the noneffective concentrations were used in combination produced a decrease in ROS formation, mainly (PhSe)(2) + GUO and (PhSe)(2) + GUO + MK-801. These results demonstrate that this combination could be effective to avoid toxic effects caused by high concentrations of QA. Furthermore, the data obtained in the ROS formation and cellular viability assays suggest different pathways in amelioration of QA toxicity present in the neurodegenerative process.

Reduction of acute hepatic damage induced by acetaminophen after treatment with diphenyl diselenide in mice.

In this study, the authors evaluated the ability of diphenyl diselenide (PhSe)(2) to reverse acute hepatic failure induced by acetaminophen (APAP) in mice. The animals received an APAP dose of 600 mg/kg intraperitoneally (i.p.), and then 1 hour later, they received 15.6 mg/kg i.p. of (PhSe)(2). Three hours after (PhSe)(2) administration, the animals were sacrificed and blood and liver samples were collected for analysis. The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured. The levels of reduced glutathione (GSH) and oxidized glutathione (GSSG), thiobarbituric acid-reactive substances (TBARS), 2',7'-dichlorofluorescein (DFC), catalase activity (CAT), and myeloperoxidase (MPO) activity were determined in the liver. A methyl-tetrazolium reduction (MTT) assay was also performed on the liver. Histopathological studies were conducted in all groups. Exposure of animals to APAP induced oxidative stress, increased lipid peroxidation (LPO), and the generation of reactive species, reduced the levels of GSH, and caused an increase in the MPO activity. Treatment with (PhSe)(2) reduced LPO and the formation of reactive species and inhibited the processes of inflammation, reducing the hepatic damage induced by APAP. The results of this study show that (PhSe)(2) is a promising therapeutic option for the treatment of acute hepatic failure.

Diphenyl diselenide diet intake improves spatial learning and memory deficits in hypothyroid female rats.

Cognitive deficits have been observed in different animal models of adult-onset hypothyroidism. Thus, this study was delineated to evaluate whether diphenyl diselenide, an organoselenium compound with neuroprotective and antioxidant properties, could afford protection against the detrimental effects of hypothyroidism on behavioral parameters. Hypothyroidism condition was induced in female rats by continuous exposure to methimazole (MTZ) at 20 mg/100 ml in the drinking water, during 3 months. MTZ-induced hypothyroid rats were fed with either standard or a diet containing 5 ppm of diphenyl diselenide for 3 months. Behavioral assessments were performed monthly, in the following order: elevated plus maze, open field and Morris water maze. The levels of thyroid hormones in the animals exposed to MTZ were lower than control until the end of experimental period. The rats exposed to MTZ had a significant weight loss from the first month, which was not modified by diphenyl diselenide supplementation. In elevated plus maze test, MTZ exposure caused a reduction on the number of entries of animals in closed arms, which was avoided by diphenyl diselenide supplementation. In Morris water maze, the parameters latency to reach the platform and distance performed to find the escape platform in the test session were significantly greater in MTZ group when compared to control. These cognitive deficits observed in MTZ-induced hypothyroid rats were restored by dietary diphenyl diselenide. The group fed with diphenyl diselenide alone exhibited a better spatial learning and memory capability in some parameters of Morris water maze when compared to the control group. In summary, our data provide evidence of the effectiveness of dietary diphenyl diselenide in improving the performance of control and hypothyroid rats in the water maze test.

Effect of repeated restraint stress and clomipramine on Na+/K+-ATPase activity and behavior in rats.

Activation of the limbic-hypothalamic-pituitary-adrenal axis (LHPA) and the release of glucocorticoids are fundamental for the adaptive response and immediate survival of an organism in reaction to acute stimuli. However, high levels of glucocorticoids in the brain may produce neuronal injury and a decrease of Na(+)/K(+)-ATPase activity, with effects on neurotransmitter signaling, neural activity, as well as the whole animal behavior. Clomipramine is a tricyclic antidepressant that inhibits the reuptake of serotonin and norepinephrine by indirect actions on the dopaminergic system and LHPA axis. Its chronic use increases the body's ability to cope with stress; however, high doses can potentiate its side effects on memory, learning, and sensory motor function. The purpose of the present study was to compare the effect of repeated restraint stress and clomipramine treatment on Na(+)/K(+)-ATPase activity and on the behavior of male rats. Changes in the behavioral response were evaluated by measuring the memory, learning, anxiety, and exploratory responses. Our results showed that exposure to repeated restraint stress reduced levels of Na(+)/K(+)-ATPase in brain structures and changed short and long-term memory, learning, and exploratory response when compared to the control group. Exposure to clomipramine treatment increased anxiety levels and reduced Na(+)/K(+)-ATPase activity in the cerebral cortex as well as short term memory, learning, and exploratory response. In conclusion, the present results provide additional evidence concerning how repeated restraint stress and clomipramine chronically administered at higher dose levels affect the neural activity and behavior of male rats.

Low concentrations of methamidophos do not alter AChE activity but modulate neurotransmitters uptake in hippocampus and striatum in vitro.

AIMS: Methamidophos (Meth) is a toxic organophosphorus compound (OP) that inhibits acetylcholinesterase enzyme (AChE) and induces neurotoxicity. As the mechanism of its neurotoxic effects is not well understood, the aim of the present study was to evaluate the effects of Meth on glutamate and gamma aminobutyric acid (GABA) uptake and correlate with cell viability and AChE and Na(+)/K(+)-ATPase enzyme activities in striatum and hippocampus slices exposed to low concentrations (0.05 to 1.0 µM) of Meth. MAIN METHODS: Hippocampal and striatal slices of rat brain were exposed to Meth for 5 min ([(3)H]Glutamate uptake) or 15 min ([(3)H]GABA uptake) for assays. The enzyme activities and cell viability were also accessed at both times in hippocampal and striatal slices and homogenates. KEY FINDINGS: At concentrations that did not inhibit AChE, Meth caused changes in glutamate uptake in striatal (0.05 and 1.0 µM Meth) and hippocampal (1.0 µM Meth) slices. GABA uptake was increased by the pesticide in striatum at 0.5 and 1.0 µM and in hippocampus at 0.05 µM. After 3.5h of Meth exposure, striatal and hippocampal cells showed no changes in viability as well as no inhibition of Na(+)/K(+)-ATPase were observed after 5 or 15 min exposure to Meth in the same brain structures. SIGNIFICANCE: Results suggest that Meth, even without changing the AChE activity can modify somehow the neurotransmitters uptake. However, further studies are necessary to clarify if this modulation in glutamate or GABA uptake may be responsible to cause some disturbance in behavior or in other neurochemical parameters following low Meth exposure in vivo.

Clomipramine treatment and repeated restraint stress alter parameters of oxidative stress in brain regions of male rats.

This study aimed to compare the effects of repeated restraint stress alone and the combination with clomipramine treatment on parameters of oxidative stress in cerebral cortex, striatum and hippocampus of male rats. Animals were divided into control and repeated restraint stress, and subdivided into treated or not with clomipramine. After 40 days of stress and 27 days of clomipramine treatment with 30 mg/kg, the repeated restraint stress alone reduced levels of Na(+), K(+)-ATPase in all tissues studied. The combination of repeated restraint stress and clomipramine increased the lipid peroxidation, free radicals and CAT activity as well as decreased levels of NP-SH in the tissues studied. However, Na(+), K(+)-ATPase level decreased in striatum and cerebral cortex and the SOD activity increased in hippocampus and striatum. Results indicated that clomipramine may have deleterious effects on the central nervous system especially when associated with repeated restraint stress and chronically administered in non therapeutic levels.