Abstract Single administration of low-dose ketamine has both acute and sustained anti-depressant effects. Sustained effect is associated with restoration of glutamatergic synapses in medial ...prefrontal cortic (mFPC) neurons. Ketamine induced profound changes in a number of molecular pathways in a mouse model for chronic stress. Cell-cell communication analyses predicted that planar-cell-polarity (PCP) signaling was decreased after chronic administration of corticosterone but increased following ketamine administration in most of the excitatory neurons. Similar decrease of PCP signaling in excitatory neurons was predicted in dorsolateral prefrontal cortical (dl-PFC) neurons of patients with major depressive disorder (MDD). We showed that the basolateral amygdala (BLA)-projecting infralimbic prefrontal cortex (IL PFC) neurons regulate immobility time in the tail suspension test and food consumption. Conditionally knocking out Celsr2 and Celsr3 or Prickle2 in the BLA-projecting IL PFC neurons abolished ketamine-induced synapse restoration and behavioral remission. Therefore, PCP proteins in IL PFC-BLA neurons mediate synapse restoration induced by of low-dose ketamine.
The local signaling mechanism which directly assembles and maintains glutamatergic synapses has not been well understood. Glutamatergic synapses are made of presynaptic and postsynaptic compartments ...with distinct sets of proteins. The planar cell polarity (PCP) pathway is highly conserved and responsible for establishing and maintaining the cell and tissue polarity along the tissue plane. The six core PCP proteins form antagonizing complexes within the cells and asymmetric intercellular complexes across neighboring cells which regulate cell‐cell interactions during planar polarity signaling. Accumulating evidence suggests that the PCP proteins play essential roles in glutamatergic synapse assembly, maintenance and function in the brain. This review summarizes the key evidence that PCP proteins may be responsible for the formation and stability of the vast majority of the glutamatergic synapses in hippocampus and medial prefrontal cortex, the progress in understanding the mechanisms of how PCP proteins assemble and maintain glutamatergic synapses and initial insights on how disruption of the function of the PCP proteins can lead to neurodegenerative, neurodevelopmental and neuropsychiatric disorders. The PCP proteins may be the missing pieces of a long‐standing puzzle and filling this gap of knowledge may provide the basis for understanding many unsolved questions in synapse biology.
Key Findings
Planar cell polarity proteins are responsible for the formation of a vast majority of glutamatergic synapses in development;
Planar cell polarity proteins are responsible for the maintenance of a vast majority of glutamatergic synapses in mature neural circuits;
Disruption of the functions of planar cell polarity proteins may underlie many nervous system disorders, particularly those that are related to synapses.
Agmatine has been recently emerged as a novel candidate to assist the conventional pharmacotherapy of depression. The acute restraint stress (ARS) is an unavoidable stress situation that may cause ...depressive-like behavior in rodents. In this study, we investigated the potential antidepressant-like effect of agmatine (10mg/kg, administered acutely by oral route) in the forced swimming test (FST) in non-stressed mice, as well as its ability to abolish the depressive-like behavior and hippocampal antioxidant imbalance induced by ARS. Agmatine reduced the immobility time in the mouse FST (1–100mg/kg) in non-stressed mice. ARS caused an increase in the immobility time in the FST, indicative of a depressive-like behavior, as well as hippocampal lipid peroxidation, and an increase in the activity of hippocampal superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities, reduced catalase (CAT) activity and increased SOD/CAT ratio, an index of pro-oxidative conditions. Agmatine was effective to abolish the depressive-like behavior induced by ARS and to prevent the ARS-induced lipid peroxidation and changes in SOD, GR and CAT activities and in SOD/CAT activity ratio. Hippocampal levels of reduced glutathione (GSH) were not altered by any experimental condition. In conclusion, the present study shows that agmatine was able to abrogate the ARS-induced depressive-like behavior and the associated redox hippocampal imbalance observed in stressed restraint mice, suggesting that its antidepressant-like effect may be dependent on its ability to maintain the pro-/anti-oxidative homeostasis in the hippocampus.
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•ARS causes a depressive-like behavior and a redox hippocampal imbalance.•ARS induced changes in TBARS, SOD, GPx, GR, CAT and SOD/CAT in the hippocampus.•Agmatine produced a significant antidepressant-like effect in the FST.•Agmatine was effective to prevent the behavioral alterations induced by ARS.•Agmatine abolished the ARS-induced changes in TBARS, SOD, GR, CAT and SOD/CAT.
Growing evidence has suggested that ascorbic acid may exhibit rapid anxiolytic and antidepressant-like effects. In this study the effects of a single administration of ascorbic acid (1 mg/kg, p.o.), ...ketamine (1 mg/kg, i.p., a fast-acting antidepressant) and fluoxetine (10 mg/kg, p.o., conventional antidepressant) were investigated on: a) behavioral performance in the novelty suppressed feeding (NSF) test; b) hippocampal synaptic protein immunocontent; c) dendritic spine density and morphology in the dorsal and ventral dentate gyrus (DG) of the hippocampus and d) hippocampal dendritic arborization. Ascorbic acid or ketamine, but not fluoxetine, decreased the latency to feed in the NSF test in mice. This effect was accompanied by increased p70S6K (Thr389) phosphorylation 1 h after ascorbic acid or ketamine treatment, although only ascorbic acid increased synapsin I immunocontent. Ketamine administration increased the dendritic spine density in the dorsal DG, but none of the treatments affected the maturation of dendritic spines in this region. In addition, both ascorbic acid and ketamine increased the dendritic spine density in the ventral DG, particularly the mature spines. Sholl analysis demonstrated no effect of any treatment on hippocampal dendritic arborization. Altogether, the results provide evidence that the behavioral and synaptic responses observed following ascorbic acid administration might occur via the upregulation of synaptic proteins, dendritic spine density, and maturation in the ventral DG, similar to ketamine. These findings contribute to understand the cellular targets implicated in its antidepressant/anxiolytic behavioral responses and support the notion that ascorbic acid may share with ketamine the ability to increase synaptic function.
•Ascorbic acid or ketamine decreased the latency to feed in the NSF test.•Ascorbic acid increased hippocampal phospho-p70S6K and synapsin I immunocontent.•Ascorbic acid and ketamine increased the dendritic spine density in the ventral DG.•Ascorbic acid may share with ketamine the ability to increase synaptic function.
We investigated the ability of agmatine to potentiate the antidepressant-like and synaptic effects of ketamine in mice. Agmatine (0.1 and 1 mg/kg, p.o.) and ketamine (1 and 10 mg/kg, i.p.) produced ...an antidepressant-like effect in the tail suspension test. The combination of agmatine (0.01 mg/kg, p.o.) and ketamine (0.1 mg/kg, i.p.), at subthreshold doses, produced an antidepressant-like effect 1 h, 24 h and 7d after treatment. Western blot analysis from prefrontal cortex tissue showed that the combined treatment, after 1 h, increased p70S6K and GluA1, and reduced synapsin 1 phosphorylation. Additionally, after 24 h, Akt, p70S6K, GluA1, and synapsin 1 phosphorylation; and PSD95 immunocontent increased (which persisted for up to 7d). Dendritic architecture analysis of the prefrontal cortex revealed that the combined treatment improved dendritic arbor complexity (after 24 h, up to 7d), and increased spine density (after 1 h, up to 24 h). Morphometric analysis revealed a filopodia-shaped dendrite spine upregulation after 1 h. A predominance of stubby, mushroom, branched and filopodia; and a reduction in thin protrusions were observed after 24 h. Finally, mushroom-shaped dendritic spines predominance increased after 7d. Agmatine potentiated ketamine's antidepressant, and dendritic arbors and spines remodeling effects in a time-dependent manner. Our data indicate Akt/p70S6K signaling as a likely target for these effects.
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•The synergism of agmatine and ketamine produces an antidepressant-like effect.•Agmatine potentiates ketamine's dendritic arbors and spines remodeling effects.•Agmatine's enhancer effects of ketamine involves Akt/S6K signaling activation.•Agmatine augments ketamine's effects in a time-dependent manner.
•Exercise elicited an antidepressant-like effect by modulating mTORC1.•Exercise increased the number of p-mTORC1-positive cells in the entire hippocampus.•Exercise raised the number of ...p-mTORC1-positive cells in the ventral hippocampus.•Exercise raised hippocampal FNDC5/irisin content independent on mTORC1 activation.
Several lines of evidence have consistently indicated that physical exercise has antidepressant effects by improving hippocampal function, although the signaling pathways underpinning these responses are not well established. Therefore, this study investigated the role of mechanistic target of rapamycin complex 1 (mTORC1) and fibronectin type III domain-containing protein 5 (FNDC5)/irisin signaling in the antidepressant-like effect of physical exercise. We showed that physical exercise (treadmill running – 45 min/day/5 days/week for 4 weeks) produced an antidepressant-like effect as indicated by a reduction on the immobility time in mice subjected to the forced swimming test (FST) without altering locomotor activity in the open field test (OFT). Rapamycin (a selective mTORC1 inhibitor, 0.2 nmol/site, i.c.v.) administration completely abolished the antidepressant-like effect of physical exercise in the FST, suggesting that mTORC1 activation plays a role for its behavioral effect. Accordingly, physical exercise increased the number of phosphorylated mTORC1 (Ser2448)-positive cells in the entire and ventral subgranular zone of the hippocampal dentate gyrus. Physical exercise was also effective in augmenting the hippocampal FNDC5/irisin immunocontent, but rapamycin administration did not alter this effect. Our results reinforce the notion that physical exercise exerts an antidepressant-like effect and identifies the mTORC1-mediated signaling pathway as a target for its behavioral effects. This study provides additional evidence that physical exercise increases hippocampal FNDC5/irisin immunocontent, but this effect seems to be independent on hippocampal mTORC1 activation. Altogether the results contribute to elucidate possible molecular targets implicated in the antidepressant effects of physical exercise and highlight the role of mTORC1 signaling for its behavioral response.
Analysis of neurotransmitters and their metabolites is useful for the diagnosis of central nervous system diseases. A liquid chromatography–tandem mass spectrometry (LC–MS/MS) method with protein ...precipitation was developed to monitor levels of adrenaline (AD), noradrenaline (NA), glutamic acid (Glu), γ-aminobutyric acid (GABA), dopamine (DA), 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in rat brain tissue. Isoprenaline was used as an internal standard (IS). Neurotransmitters and metabolites were eluted with a reverse phase column under gradient conditions through a mobile phase consisting of 0.2% formic acid water solution/acetonitrile. The compounds were detected and quantified by LC–MS/MS with positive or negative electrospray ionization, which operates in multiple-reaction monitoring mode. The method was linear or polynomial (R2>0.99) for AD, NA, Glu, GABA, DA, 5-HT, 5-HIAA, and MHPG in the range of 0.25–200, 0.5–200, 250–20,000, 250–20,000, 0.25–200, 10–3000, 1–50, and 1–50ng/mL, respectively. The validation assays for accuracy and precision, matrix effect, extraction recovery, stability and carry-over of the samples for neurotransmitters and metabolites were consistent with the requirements of regulatory agencies. The method enables rapid quantification of neurotransmitters and their metabolites and has been applied in the nuclear factor (erythroid 2-derived)–like 2 (Nrf2) knockout mouse model of depression.
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•Liquid chromatography–mass spectrometry used to monitor neurotransmitter and metabolite levels•Protein precipitation as sample preparation in rat brain matrix•Method validated according to the recommendations of regulatory agencies•Rapid quantification of neurotransmitters and metabolites to diagnose neurological diseases•Application of the method to the murine Nrf2 depression model
Guanosine is a guanine-based purine that modulates glutamate uptake and exerts neurotrophic and neuroprotective effects. In a previous study, our group demonstrated that this endogenous nucleoside ...displays antidepressant-like properties in a predictive animal model. Based on the role of oxidative stress in modulating depressive disorders as well as on the association between the neuroprotective and antioxidant properties of guanosine, here we investigated if its antidepressant-like effect is accompanied by a modulation of hippocampal oxidant/antioxidant parameters. Adult Swiss mice were submitted to an acute restraint stress protocol, which is known to cause behavioral changes that are associated with neuronal oxidative damage. Animals submitted to ARS exhibited an increased immobility time in the forced swimming test (FST) and the administration of guanosine (5mg/kg, p.o.) or fluoxetine (10mg/kg, p.o., positive control) before the exposure to stressor prevented this alteration. Moreover, the significantly increased levels of hippocampal malondialdehyde (MDA; an indicator of lipid peroxidation), induced by ARS were not observed in stressed mice treated with guanosine. Although no changes were found in the hippocampal levels of reduced glutathione (GSH), the group submitted to ARS procedure presented enhanced glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) activities and reduced catalase (CAT) activity in the hippocampus. Guanosine was able to prevent the alterations in GPx, GR, CAT activities, and in SOD/CAT activity ratio, but potentiated the increase in SOD activity elicited by ARS. Altogether, the present findings indicate that the observed antidepressant-like effects of guanosine might be related, at least in part, to its capability of modulating antioxidant defenses and mitigating hippocampal oxidative damage induced by ARS.
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•Guanosine treatment abolishes the stress-induced behavioral alterations in the FST.•The protective action is accompanied by a reduced hippocampal oxidative damage.•Guanosine prevented the increased GR and GPx activities induced by ARS exposure.•Guanosine caused an increase in SOD activity in restraint-stressed mice.•The increased SOD/CAT induced by ARS procedure was prevented by guanosine.
Abstract Major depressive disorder is the most common psychiatric disorder with lifetime prevalence of up to 20% worldwide. It is responsible for more years lost to disability than any other ...disorder. Despite the fact that current available antidepressant drugs are safe and effective, they are far from ideal. In addition to the need to administer the drugs for weeks or months to obtain clinical benefit, side effects are still a serious problem. Agmatine is an endogenous polyamine synthesized by the enzyme arginine decarboxylase. It modulates several receptors and is considered as a neuromodulator in the brain. In this review, studies demonstrating the antidepressant effects of agmatine are presented and discussed, as well as, the mechanisms of action related to these effects. Also, the potential beneficial effects of agmatine for the treatment of other neurological disorders are presented. In particular, we provide evidence to encourage future clinical studies investigating agmatine as a novel antidepressant drug.
•Folic acid abrogates the depressive-like behavior induced by TNF-α in mice.•Folic acid and antidepressants have a synergistic effect in the TST.•The antidepressant-like effect of folic acid involves ...inhibition of NMDA receptors.•The antidepressant-like effect of folic acid depends on reduced NO synthesis.•Akt modulation may be involved in the antidepressant-like action of folic acid.
Folic acid has been reported to exert antidepressant effects, but its ability to abrogate the depressive-like behavior and signaling pathways alterations elicited by an inflammatory model of depression remains to be established. This study examined: a) the efficacy of folic acid in a mouse model of depression induced by tumor necrosis factor (TNF-α); b) whether the administration of subthreshold doses of folic acid and antidepressants (fluoxetine, imipramine, and bupropion), MK-801, or 7-nitroindazole cause antidepressant-like effects; c) the effects of TNF-α and/or folic acid on hippocampal p38MAPK, Akt, ERK, and JNK phosphorylation. Folic acid reduced the immobility time in the tail suspension test (TST) in control mice (10–50 mg/kg, p.o) and abolished the depressive-like behavior elicited by TNF-α (0.001 fg/site, i.c.v.) in this test (1–50 mg/kg, p.o). Coadministration of subthreshold doses of folic acid (1 mg/kg, p.o.) and fluoxetine, imipramine, bupropion, MK-801, or 7-nitroindazole produced an antidepressant-like effect in mice exposed or not to TNF-α. TNF-α-treated mice presented increased p38MAPK phosphorylation and decreased Akt phosphorylation, and the later effect was prevented by folic acid (10 mg/kg, p.o.). Additionally, ERK1 phosphorylation was increased in mice treated with TNF-α + folic acid (1 mg/kg), but no effects on ERK2 or JNK1/2/3 phosphorylation were found in any group. The results indicate the efficacy of folic acid to counteract the depressive-like behavior induced by a pro-inflammatory cytokine, an effect that might be associated with the activation of monoaminergic systems, inhibition of N-methyl-d-aspartate (NMDA) receptors and nitric oxide (NO) synthesis, as well as Akt modulation.
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