Activation Of AMPA Receptors Research Articles

Jujuboside B inhibits febrile seizure by modulating AMPA receptor activity

Ethnopharmacological relevanceFebrile seizure is a common neurologic disorder with limited treatment occurring in infants and children under the age of five. Jujuboside B (JuB) is a main bioactive saponin component isolated from the Chinese anti-insomnia herbal medicine Ziziphi Spinosae Semen (ZSS), seed of Ziziphus jujuba Mill, which has been proved to exhibit neuroprotective effects recently. Aim of the studyIn this study, we aimed at elucidating the effect of JuB on suppressing febrile seizure and the potential mechanisms. MethodsElectroencephalogram (EEG) recording was used to monitor the severity of febrile seizures. The JuB in the brain was identified by mass spectrometry. Neuronal excitability was investigated using patch clamp. ResultsJuB (30 mg/kg) significantly prolonged seizure latency and reduced the severity in hyperthermia-induced seizures model mice. Hippocampal neuronal excitability was significantly decreased by JuB. And JuB significantly reduced the excitatory synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-iso-xazolepropionic acid receptor (AMPAR), including evoked excitatory postsynaptic currents (eEPSCs), and miniature EPSCs (mEPSCs) in hippocampal neurons. Furthermore, JuB also significantly inhibited recombinant GluA1 and GluA2 mediated AMPA current in HEK293 cell and decreased the upregulation of [Ca2+]i induced by AMPA in primary cultured cortex neurons. ConclusionsJuB suppressed the excitability of hippocampal neurons by inhibiting the activity of AMPAR and reducing the intracellular free calcium, thereby relieving febrile seizures.

Neuroprotective Effect of the Neuropeptide Cycloprolylglycine Depends on AMPA- and TrkB-Receptor Activation

Previously, we have shown that the endogenous neuropeptide cycloprolylglycine (CPG) is the positive modulator of AMPA receptors and revealed the dependence of its anxiolytic and antihypoxic action on BDNF/Trk signaling. In the present work, we for the first time conducted in vitro experiments using the AMPA receptor blockers DNQX and GYKI 52466 and the Trk receptor blocker K252a. It is shown that the neuroprotective effect of CPG depends on the activation of both AMPA and Trk receptors.

α-Lipoic Acid Derivatives as Allosteric Modulators for Targeting AMPA-Type Glutamate Receptors' Gating Modules.

The ionotropic glutamate receptor subtype α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) is responsible for most excitatory transmission in the brain. AMPA receptor function is altered in numerous neurological illnesses, making AMPA receptors appealing therapeutic targets for clinical intervention. Alpha-Lipoic acid (α-LA) is a naturally occurring compound, which functions as a co-factor in metabolism and energy production. α-LA is an antioxidant with various benefits in treating diabetes, including managing symptomatic diabetic neuropathy. This study will test a novel and innovative strategy to synthesize a new isomer of lipoic acid (R-LA) derivatives (bifunctional NO-donor/antioxidant) in one chemical on homomeric and heteromeric AMPA receptor subunits. We used patch-clamp electrophysiology to examine LA derivatives expressed in human embryonic kidney 293 cells (HEK293) for inhibition and changes in desensitization or deactivation rates. LA derivatives were shown to be potent antagonists of AMPA receptors, with an 8-11-fold reduction in AMPA receptor currents seen following the delivery of the compounds. Furthermore, the LA derivatives influenced the rates of desensitization and deactivation of AMPA receptors. Based on our results, especially given that α-LA is closely connected to the nervous system, we may better understand using AMPA receptors and innovative drugs to treat neurological diseases associated with excessive activation of AMPA receptors.

Theta patterns of stimulation induce synaptic and intrinsic potentiation in O-LM interneurons.

Brain oscillations have long-lasting effects on synaptic and cellular properties. For instance, synaptic stimulation at theta (θ) frequency induces persistent depression of both excitatory synaptic transmission and intrinsic excitability in CA1 principal neurons. However, the incidence of θ activity on synaptic transmission and intrinsic excitability in hippocampal GABAergic interneurons is unclear. We report here the induction of both synaptic and intrinsic potentiation in oriens-lacunosum moleculare (O-LM) interneurons following stimulation of afferent glutamatergic inputs in the θ frequency range (∼5 Hz). Long-term synaptic potentiation (LTP) is induced by synaptic activation of calcium-permeable AMPA receptors (CP-AMPAR), whereas long-term potentiation of intrinsic excitability (LTP-IE) results from the mGluR1-dependent down-regulation of Kv7 voltage-dependent potassium channel and hyperpolarization activated and cyclic nucleotide-gated (HCN) channel through the depletion of phosphatidylinositol-4,5-biphosphate (PIP2). LTP and LTP-IE are reversible, demonstrating that both synaptic and intrinsic changes are bidirectional in O-LM cells. We conclude that synaptic activity at θ frequency induces both synaptic and intrinsic potentiation in O-LM interneurons, i.e., the opposite of what is typically seen in glutamatergic neurons.

Sex- and age-dependent effects of chronic corticosterone exposure on depressive-like, anxiety-like, and fear-related behavior: Role of amygdala glutamate receptors in the rat.

Persistent glucocorticoid elevation consistent with chronic stress exposure can lead to psychopathology, including mood and anxiety disorders. Women and stress-exposed adolescents are more likely to be diagnosed with mood disorders, suggesting that sex and age are important factors in determining vulnerability, though much remains to be determined regarding the mechanisms underlying this risk. Thus, the aim of the present experiments was to use the chronic corticosterone (CORT) exposure paradigm, a model of depression-like behavior that has previously been established primarily in adult males, to determine the mood-related effects of CORT in female and adolescent rats. Depression- and anxiety-like effects in adulthood were determined using the sucrose preference (SPT), the forced swim test (FST), the elevated plus maze, and fear conditioning. Basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) glutamate receptor subunit levels were then measured. In a subsequent experiment, adult male and female rats were tested for the effects of pharmacological activation (via AMPA) or inhibition (via NBQX) of AMPA receptors in the BLA on behavior in the FST. Overall, females showed reduced anxiety- and depressive-like behaviors relative to males. However, females treated with CORT in adolescence, but not adulthood, had increased immobility in the FST, indicative of depression-like behavior. In contrast, CORT did not alter behavior in adolescent-treated males, though the previously reported depression-like effect of adult CORT exposure was observed. Control females had higher expression of the AMPA receptor subunits GluA1 and GluA2/3 selectively in the BLA relative to males. Adolescent CORT treatment, however, decreased BLA GluA1 and GluA2/3 expression in females, but increased expression in males, consistent with the direction of depression-like behavioral effects. Male and female rats also demonstrated opposing patterns of response to BLA AMPA receptor modulation in the FST, with AMPA infusion magnifying the sex difference of decreased immobility in females. Overall, these experiments show that increased glutamate receptor function in the BLA may decrease the risk of developing depressive-like behavior, further supporting efforts to target glutamatergic receptors for the treatment of stress-related psychiatric disorders. These findings also support further focus on sex as a biological variable in neuropsychiatric research.

Platinum nanoparticle-based microreactors protect against the behavioral and neurobiological consequences of chronic stress exposure

Excitotoxicity is described as the exacerbated activation of glutamate AMPA and NMDA receptors that leads to neuronal damage, and ultimately to cell death. Astrocytes are responsible for the clearance of 80–90% of synaptically released glutamate, preventing excitotoxicity. Chronic stress renders neurons vulnerable to excitotoxicity and has been associated to neuropsychiatric disorders, i.e., anxiety. Microreactors containing platinum nanoparticles (Pt-NP) and glutamate dehydrogenase have shown in vitro activity against excitotoxicity. The purpose of the present study was to investigate the in vivo effects of these microreactors on the behavioral and neurobiological effects of chronic stress exposure. Rats were either unstressed or exposed for 2 weeks to an unpredictable chronic mild stress paradigm (UCMS), administered intra-ventral hippocampus with the microreactors (with or without the blockage of astrocyte functioning), and seven days later tested in the elevated T-maze (ETM; Experiment 1). The ETM allows the measurement of two defensive responses, avoidance and escape, in terms of psychopathology respectively related to generalized anxiety and panic disorder. Locomotor activity in an open field was also measured. Since previous evidence shows that stress inhibits adult neurogenesis, we evaluated the effects of the different treatments on the number of cells expressing the marker of migrating neuroblasts doublecortin (DCX) in the dorsal and ventral hippocampus (Experiment 2). Results showed that UCMS induces anxiogenic effects, increases locomotion, and decreases the number of DCX cells in the dorsal and ventral hippocampus, effects that were counteracted by microreactor administration. This is the first study to demonstrate the in vivo efficacy of Pt-NP against the behavioral and neurobiological effects of chronic stress exposure.

Induction of Activity-Dependent Plasticity at Auditory Nerve Synapses.

Exposure to nontraumatic noise in vivo drives long-lasting changes in auditory nerve synapses, which may influence hearing, but the induction mechanisms are not known. We mimicked activity in acute slices of the cochlear nucleus from mice of both sexes by treating them with high potassium, after which voltage-clamp recordings from bushy cells indicated that auditory nerve synapses had reduced EPSC amplitude, quantal size, and vesicle release probability (P r). The effects of high potassium were prevented by blockers of nitric oxide (NO) synthase and protein kinase A. Treatment with the NO donor, PAPA-NONOate, also decreased P r, suggesting NO plays a central role in inducing synaptic changes. To identify the source of NO, we activated auditory nerve fibers specifically using optogenetics. Strobing for 2 h led to decreased EPSC amplitude and P r, which was prevented by antagonists against ionotropic glutamate receptors and NO synthase. This suggests that the activation of AMPA and NMDA receptors in postsynaptic targets of auditory nerve fibers drives release of NO, which acts retrogradely to cause long-term changes in synaptic function in auditory nerve synapses. This may provide insight into preventing or treating disorders caused by noise exposure.SIGNIFICANCE STATEMENT Auditory nerve fibers undergo long-lasting changes in synaptic properties in response to noise exposure in vivo, which may contribute to changes in hearing. Here, we investigated the cellular mechanisms underlying induction of synaptic changes using high potassium and optogenetic stimulation in vitro and identified important signaling pathways using pharmacology. Our results suggest that auditory nerve activity drives postsynaptic depolarization through AMPA and NMDA receptors, leading to the release of nitric oxide, which acts retrogradely to regulate presynaptic neurotransmitter release. These experiments revealed that auditory nerve synapses are unexpectedly sensitive to activity and can show dramatic, long-lasting changes in a few hours that could affect hearing.

Antinociceptive and Analgesic Effects of (2R,6R)-Hydroxynorketamine.

Commonly used pain therapeutics, such as opioid medications, exert dangerous side effects and lack effectiveness in treating some types of pain. Ketamine is also used to treat pain, but side effects limit its widespread use. (2R,6R)-hydroxynorketamine (HNK) is a ketamine metabolite that potentially shares some beneficial behavioral effects of its parent drug without causing significant side effects. This study compared the profile and potential mechanisms mediating the antinociception activity of ketamine and (2R,6R)-HNK in C57BL/6J mice. Additionally, this study compared the reversal of mechanical allodynia by (2R,6R)-HNK with gabapentin in a model of neuropathic pain. Unlike the near-immediate and short-lived antinociception caused by ketamine, (2R,6R)-HNK produced late-developing antinociception 24 hours following administration. Pharmacological blockade of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors with 2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX) prevented the initiation and expressionof (2R,6R)-HNK antinociception, suggesting the involvement of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-dependent glutamatergic mechanisms in the pain reduction-like responses. Blockade of opioid receptors with naltrexone partially prevented the antinociceptive effect of ketamine but was ineffective against (2R,6R)-HNK. Furthermore, (2R,6R)-HNK did not produce dystaxia, even when tested at doses five times greater than those needed to produce antinociception, indicating a superior safety profile for (2R,6R)-HNK over ketamine. Additionally, (2R,6R)-HNK reversed mechanical allodynia in a spared nerve injury model of neuropathic pain with similar short-term efficacy to gabapentin (within 4 hours) while outperforming gabapentin 24 hours after administration. These findings support the further study of (2R,6R)-HNK as a potentially valuable agent for treating different types of pain and establish certain advantages of (2R,6R)-HNK treatment over ketamine and gabapentin in corresponding assays for pain. SIGNIFICANCE STATEMENT: The ketamine metabolite (2R,6R)-HNK produced antinociception in male and female mice 24 hours after administration via activation of AMPA receptors. The effects of (2R,6R)-HNK differed in time course and mechanism and presented a better safety profile than ketamine. (2R,6R)-HNK also reversed allodynia in SNI-operated animals within 4 hours of treatment onset, with a duration of effect lasting longer than gabapentin. Taken together, (2R,6R)-HNK demonstrates the potential for development as a non-opioid analgesic drug.

Expression and Development of TARP γ-4 in Embryonic Zebrafish

Fast excitatory synaptic transmission in the CNS is mediated by the neurotransmitter glutamate, binding to and activating AMPA receptors (AMPARs). AMPARs are known to interact with auxiliary proteins that modulate their behavior. One such family of proteins is the transmembrane AMPAR-related proteins, known as TARPs. Little is known about the role of TARPs during development or about their function in nonmammalian organisms. Here, we report on the presence of TARP γ-4 in developing zebrafish. We find that zebrafish express 2 forms of TARP γ-4: γ-4a and γ-4b as early as 12 h post-fertilization. Sequence analysis shows that both γ-4a and γ-4b shows great level of variation particularly in the intracellular C-terminal domain compared to rat, mouse, and human γ-4. RT-qPCR showed a gradual increase in the expression of γ-4a throughout the first 5 days of development, whereas γ-4b levels were constant until day 5 when levels increased significantly. Knockdown of TARP γ-4a and γ-4b via either splice-blocking morpholinos or translation-blocking morpholinos resulted in embryos that exhibited deficits in C-start escape responses, showing reduced C-bend angles. Morphant larvae displayed reduced bouts of swimming. Whole-cell patch-clamp recordings of AMPAR-mediated currents from Mauthner cells showed a reduction in the frequency of mEPCs but no change in amplitude or kinetics. Together, these results suggest that γ-4a and γ-4b are required for proper neuronal development.

The cognitive effects of esketamine: what do we know so far?

IntroductionEsketamine is an S-enantiomer of ketamine approved by the EMA for treatment-resistant depression (TRD). As an NMDA receptor antagonist, its administration results in increase of glutamate release and AMPA receptor activation, supporting both rapid-onset and long-term antidepressant effects. Short-term tolerability seems acceptable but major concerns remain regarding long-term safety, specifically regarding potential neurocognitive toxicity.ObjectivesTo clarify the potential short and long-term cognitive beneficial-effects and side-effects of esketamine.MethodsResearch was made using the Medline database, through the Pubmed search engine, using the keywords: “esketamine”, “cognition”. Only randomized-controlled trials were considered.ResultsOne study focused on the effects of intranasal esketamine (INE) on cognitive functioning in 24 healthy individuals, who were evaluated pre- and postdose (40 min, 2h, 4h and 6h). The results showed a decline in cognitive performance at 40 min postdose, returning to comparable levels as placebo by 2h postdose. Another study, with a follow-up of 1 year, involving 802 TRD patients, accessed the long-term safety of INE. In patients aged <65 years-old, performance on all cognitive tests remained stable or slightly improved from baseline during long-term treatment. In patients ≥ 65 years-old, the mean performance on all tests improved or remained stable, while the simple and choice reaction time began slowing at week 20.ConclusionsEsketamine has proven to be a promising new option for the treatment of TRD and available studies have shown promising results regarding patients’ cognitive function. Larger clinical trials are needed to further evaluate its short-term and long-term cognitive effects.DisclosureNo significant relationships.

A light-induced small G-protein gem limits the circadian clock phase-shift magnitude by inhibiting voltage-dependent calcium channels.

Calcium signaling is pivotal to the circadian clockwork in the suprachiasmatic nucleus (SCN), particularly in rhythm entrainment to environmental light-dark cycles. Here, we show that a small G-protein Gem, an endogenous inhibitor of high-voltage-activated voltage-dependent calcium channels (VDCCs), is rapidly induced by light in SCN neurons via the calcium (Ca2+)-mediated CREB/CRE transcriptional pathway. Gem attenuates light-induced calcium signaling through its interaction with VDCCs. The phase-shift magnitude of locomotor activity rhythms by light, at night, increases in Gem-deficient (Gem-/-) mice. Similarly, in SCN slices from Gem-/- mice, depolarizing stimuli induce larger phase shifts of clock gene transcription rhythms that are normalized by the application of an L-type VDCC blocker, nifedipine. Voltage-clamp recordings from SCN neurons reveal that Ca2+ currents through L-type channels increase in Gem-/- mice. Our findings suggest that transcriptionally activated Gem feeds back to suppress excessive light-evoked L-type VDCC activation, adjusting the light-induced phase-shift magnitude to an appropriate level in mammals.

The action of Con-ikot-ikot toxin on single AMPA-type glutamate receptors.

Conotoxins are a large group of naturally occurring toxic peptides produced by the predatory sea snails of the genus Conus. Many of these toxins target ion channels, often with high specificity and affinity. As such, they have proven to be invaluable for basic research, as well as acting as leads for therapeutic strategies. Con-ikot-ikot is the only conotoxin so far identified that targets AMPA-type glutamate receptors, the main mediators of excitatory neurotransmission in the vertebrate brain. Here, we describe how the toxin modifies the activity of AMPA receptors at the single-channel level. The toxin binds to the AMPA receptor with EC50 of 5 nM, and once bound takes minutes to wash out. As shown previously, it effectively blocks desensitization of AMPA receptors; however, compared to other desensitization blockers, it is a poor stabilizer of the open channel because toxin-bound AMPA receptors undergo frequent brief closures. We propose that this is a direct consequence of the toxin's unique binding mode to the ligand-binding domains (LBDs). Unlike other blockers of desensitization, which stabilize individual dimers within an AMPA receptor tetramer, the toxin immobilizes all four LBDs of the tetramer. This result further emphasizes that quaternary reorganization of independent LBD dimers is essential for the full activity of AMPA receptors.

Paraquat-induced intracellular Zn2+ dysregulation causes dopaminergic degeneration in the substantia nigra, but not in the striatum

Parkinson's disease is characterized by a selective death of nigrostriatal dopaminergic neurons, while the difference in the vulnerability to the death between the substantia nigra pars compacta (SNpc) and the striatum is poorly understood. Here we tested the difference focused on paraquat (PQ)-induced intracellular Zn2+ toxicity via extracellular glutamate accumulation. When PQ was locally injected into the SNpc and the striatum, dopaminergic degeneration was observed in the SNpc, but not in the striatum. Intracellular hydrogen peroxide (H2O2) produced by PQ was increased in both the SNpc and the striatum. In contrast, extracellular glutamate accumulation was observed only in the SNpc and rescued in the presence of N-(p-amylcinnamoyl)anthranilic acid (ACA), a blocker of the transient receptor potential melastatin 2 (TRPM2) cation channels. PQ increased intracellular Zn2+ level in the SNpc, but not in the striatum. The increase was rescued by 1-naphthyl acetyl spermine (NASPM), a selective blocker of Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptors. PQ-induced dopaminergic degeneration in the SNpc was rescued by ACA, NASPM, and GBR, a dopamine reuptake inhibitor. The present study indicates intracellular H2O2 produced by PQ, which is taken up through dopamine transporters, is retrogradely transported to presynaptic glutamatergic terminals, activates TRPM2 channels, accumulates glutamate in the extracellular compartment, and induces intracellular Zn2+ dysregulation via Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptor activation, resulting in dopaminergic degeneration in the SNpc. However, H2O2 signaling is not the case in the striatum. Paraquat-induced Zn2+ dysregulation plays a key role for neurodegeneration in the SNpc, but not in the striatum.

Activation of AMPA Receptors in the Lateral Habenula Produces Anxiolytic Effects in a Rat Model of Parkinson's Disease.

Background: Parkinson’s disease (PD) is commonly accompanied with anxiety disorder, however, the mechanisms underlying PD-mediated anxiety remain elusive. The lateral habenula (LHb) is a critical brain region that influences the activity of the monoaminergic system in the midbrain and consequently modulates anxiety. Most neurons in the LHb express AMPA receptors (AMPARs). The PD model for the pharmacological intervention of AMPA receptors was established by the unilateral lesion of the substantia nigra pars compacta (SNc) with 6-hydroxydopamine (6-OHDA). Methods: The AMPAR agonist (S)-AMPA and antagonist NBQX were microinjected into the LHb, respectively, to examine whether anxiety-like behaviors were altered in sham-operated and SNc-lesion rats, measured with the paradigms of the open-field test (OPT) and elevated plus maze (EPM). Furthermore, dopamine (DA) and 5-hydroxytryptamine (5-HT) levels in the basolateral amygdala (BLA) were measured using in vivo microdialysis immediately following the injections of (S)-AMPA and NBQX into the LHb. Results: Activation of LHb AMPA receptors by (S)-AMPA produced anxiolytic-like behaviors and enhanced the extracellular DA and 5-HT in the BLA. Conversely, NBQX induced anxiety-like effects and suppressed the extracellular DA and 5-HT in the BLA. In addition, the minimal doses inducing the effects in the SNc-lesion rats were lower than those in sham-operated rats. Conclusion: These findings suggest that the effects of AMPA receptors in the LHb on anxiety-like behaviors likely involve the extracellular levels of DA and 5-HT in the BLA. The present results may improve our understanding of the neuropathology and/or treatment of PD.

The Toll-like receptor 4 antagonist TAK-242 induces antidepressant-like effects in a rat learned helplessness model of depression through BDNF-TrkB signaling and AMPA receptor activation

Finding from animal models of depression indicated that Toll-like receptor 4 (TLR4) is associated with the pathophysiology of depression. Herein, the TLR4 antagonists TAK-242 and baicalin induced antidepressant-like effects in a rat learned helplessness model of depression. The antidepressant-like effects of both TLR4 antagonists were blocked by the TrkB inhibitor ANA-12. Also, the antidepressant-like effects of TAK-242 were blocked by the treatment with AMPA receptor antagonist NBQX. The antidepressant-like effects of the TLR4 antagonist TAK-242 involves BDNF-TrkB signaling and AMPA receptor activation.

Combined Administration of (R)-Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Induces Rapid and Sustained Effects in the CUMS Model of Depression via a TrkB/BDNF-Dependent Mechanism.

Ketamine is an effective, rapid-acting antidepressant drug (RAAD), but it induces side effects. To overcome these challenges, attempts have been made to use safer enantiomer ((R)-ketamine) or mGlu2/3 receptor antagonists, which induce ketamine-like effects and enhance its action. Here, we propose combining these two strategies to investigate the antidepressant-like effects of low doses of two ketamine enantiomers in combination with a low dose of the mGlu2/3 receptor antagonist LY341495. Rapid and sustained antidepressant-like effects were assessed in C57BL/6J mice using the tail suspension test (TST) and the chronic unpredictable mild stress (CUMS) model of depression in stress-naïve mice. ELISA was used to measure BDNF levels. In the TST, low doses of both (S)-ketamine and (R)-ketamine were potentiated by a subeffective dose of LY341495. However, in the CUMS model, only (R)-ketamine was able to induce long-lasting anti-apathetic and anti-anhedonic effects when coadministered with low-dose LY341495. The mechanism of this drug combination was dependent on BDNF and AMPA receptor activity. ELISA results suggest that the hippocampus might be the site of this action. MGlu2/3 receptor antagonists, in combination with (R)-ketamine, may serve as potential RAADs, with a high efficiency and low risk of side effects.

Intracellular hydrogen peroxide produced by 6-hydroxydopamine is a trigger for nigral dopaminergic degeneration of rats via rapid influx of extracellular Zn2+

To elucidate the mechanism and significance of 6-hydroxydopamine (6-OHDA)-induced Zn2+ toxicity, which is involved in neurodegeneration in the substantia nigra pars compacta (SNpc) of rats, we postulated that intracellular hydrogen peroxide (H2O2) produced by 6-OHDA is a trigger for intracellular Zn2+ dysregulation in the SNpc. Intracellular H2O2 level elevated by 6-OHDA in the SNpc was completely inhibited by co-injection of GBR 13069 dihydrochloride (GBR), a dopamine reuptake inhibitor, suggesting that 6-OHDA taken up through dopamine transporters produces H2O2 in the intercellular compartment of dopaminergic neurons. When the SNpc was perfused with H2O2, glutamate accumulated in the extracellular compartment and the accumulation was inhibited in the presence of N-(p-amylcinnamoyl)anthranilic acid (ACA), a blocker of the transient receptor potential melastatin 2 (TRPM2) channels. In addition to 6-OHDA, H2O2 also induced intracellular Zn2+ dysregulation via AMPA receptor activation followed by nigral dopaminergic degeneration. Furthermore, 6-OHDA-induced nigral dopaminergic degeneration was completely inhibited by co-injection of either HYDROP, an intracellular H2O2 scavenger or GBR into the SNpc. The present study indicates that H2O2 is produced by 6-OHDA taken up through dopamine transporters in the SNpc, is retrogradely transported to presynaptic glutamatergic terminals, activates TRPM2 channels, accumulates glutamate in the extracellular compartment, and induces intracellular Zn2+ dysregulation via AMPA receptor activation, resulting in nigral dopaminergic degeneration prior to movement disorder. It is likely that intracellular H2O2, but not extracellular H2O2, is a key trigger for nigral dopaminergic degeneration via intracellular Zn2+ dysregulation.

Slow excitatory synaptic currents generated by AMPA receptors.

Decades of literature indicate that the AMPA-type glutamate receptor is among the fastest acting of all neurotransmitter receptors. These receptors are located at excitatory synapses, and conventional wisdom says that they activate in hundreds of microseconds, deactivate in milliseconds due to their low affinity for glutamate and also desensitize profoundly. These properties circumscribe AMPA receptor activation in both space and time. However, accumulating evidence shows that AMPA receptors can also activate with slow, indefatigable responses. They do so through interactions with auxiliary subunits that are able promote a switch to a high open probability, high-conductance 'superactive' mode. In this review, we show that any assumption that this phenomenon is limited to heterologous expression is false and rather that slow AMPA currents have been widely and repeatedly observed throughout the nervous system. Hallmarks of the superactive mode are a lack of desensitization, resistance to competitive antagonists and a current decay that outlives free glutamate by hundreds of milliseconds. Because the switch to the superactive mode is triggered by activation, AMPA receptors can generate accumulating 'pedestal' currents in response to repetitive stimulation, constituting a postsynaptic mechanism for short-term potentiation in the range 5-100Hz. Further, slow AMPA currents span 'cognitive' time intervals in the 100ms range (theta rhythms), of particular interest for hippocampal function, where slow AMPA currents are widely expressed in a synapse-specific manner. Here, we outline the implications that slow AMPA receptors have for excitatory synaptic transmission and computation in the nervous system.

Reactive Astrocytosis in a Mouse Model of Chronic Polyamine Catabolism Activation.

Background: In the brain, polyamines are mainly synthesized in neurons, but preferentially accumulated in astrocytes, and are proposed to be involved in neurodegenerative/neuroinflammatory disorders and neuron injury. A transgenic mouse overexpressing spermine oxidase (SMOX, which specifically oxidizes spermine) in the neocortex neurons (Dach-SMOX mouse) was proved to be a model of increased susceptibility to excitotoxic injury. Methods: To investigate possible alterations in synapse functioning in Dach-SMOX mouse, both cerebrocortical nerve terminals (synaptosomes) and astrocytic processes (gliosomes) were analysed by assessing polyamine levels, ezrin and vimentin content, glutamate AMPA receptor activation, calcium influx, and catalase activity. Results: The main findings are as follows: (i) the presence of functional calcium-permeable AMPA receptors in synaptosomes from both control and Dach-SMOX mice, and in gliosomes from Dach-SMOX mice only; (ii) reduced content of spermine in gliosomes from Dach-SMOX mice; and (iii) down-regulation and up-regulation of catalase activity in synaptosomes and gliosomes, respectively, from Dach-SMOX mice. Conclusions: Chronic activation of SMOX in neurons leads to major changes in the astrocyte processes including reduced spermine levels, increased calcium influx through calcium-permeable AMPA receptors, and stimulation of catalase activity. Astrocytosis and the astrocyte process alterations, depending on chronic activation of polyamine catabolism, result in synapse dysregulation and neuronal suffering.

Malpigmentation of Common Sole (Solea solea) during Metamorphosis Is Associated with Differential Synaptic-Related Gene Expression.

Simple SummaryCommon sole (Solea solea) is an important species for the aquaculture industry. Defects in pigmentation of the species are very common in farmed conditions. Differences in gene expression between normally pigmented juveniles and those that present both sides full pigmented, ocular and blind, were investigated. Differentially expressed transcripts were functionally annotated, and gene ontology was carried out. The results indicated that ambicolorated juveniles showed a significant upregulation of genes involved in the signal transmission at the synaptic level and regulation of ion channels, affecting the plasticity and the development of the synapses, as well as the transmission of signals or ions through channels.In farmed flatfish, such as common sole, color disturbances are common. Dyschromia is a general term that includes the color defects on the blind and ocular sides of the fish. The purpose was to examine the difference in gene expression between normal pigmented and juveniles who present ambicoloration. The analysis was carried out with next-generation sequencing techniques and de novo assembly of the transcriptome. Transcripts that showed significant differences (FDR < 0.05) in the expression between the two groups, were related to those of zebrafish (Danio rerio), functionally identified, and classified into categories of the gene ontology. The results revealed that ambicolorated juveniles exhibit a divergent function, mainly of the central nervous system at the synaptic level, as well as the ionic channels. The close association of chromophore cells with the growth of nerve cells and the nervous system was recorded. The pathway, glutamate binding–activation of AMPA and NMDA receptors–long-term stimulation of postsynaptic potential–LTP (long term potentiation)–plasticity of synapses, appears to be affected. In addition, the development of synapses also seems to be affected by the interaction of the LGI (leucine-rich glioma inactivated) protein family with the ADAM (a disintegrin and metalloprotease) ones.