Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Research Articles

Subunit composition of glutamate and gamma-aminobutyric acid receptors in status epilepticus

To describe the subunit composition of glutamate and gamma-aminobutyric acid (GABA) receptors in brain tissue from patients with different types of status epilepticus. The subunit composition of glutamate and GABA receptors was analyzed in: (1) surgical brain samples from three patients with refractory convulsive status epilepticus, three patients with electrical status epilepticus in sleep, and six patients with refractory epilepsy, and (2) brain autopsy samples from four controls who died without neurological disorders. Subunit expression was quantified with Western blotting and messenger ribonucleic acid (mRNA) expression was quantified with reverse polymerase chain reaction. Western blot analysis demonstrated the following patterns (as compared to controls): (1) alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors: elevated GluA1/GluA2 ratio in electrical status epilepticus in sleep (465%±119) and refractory epilepsy (329%±125; p<0.01); (2) N-methyl-d-aspartate (NMDA) receptors: increased GluN2B/GluN2A ratio in electrical status epilepticus in sleep (3682%±1000) and refractory convulsive status epilepticus (3520%±751; p<0.05); (3) GABA receptors: elevated α2/α1 ratio in refractory epilepsy (321%±138; p<0.05) and refractory convulsive status epilepticus (346%±74; p<0.05); and (4) patients with underlying malformation of cortical development had increased ratios in GluA1/GluA2 (382%±149; p<0.01), GluN2B/GluN2A (3321%±1581; p<0.05) and α2/α1 (303%±86; p<0.01). Quantification of mRNA demonstrated an elevated GABRA2/GABRA1 ratio in refractory epilepsy (712; p<0.05) as compared to controls. The subunit composition of glutamate and GABA receptors in patients with status epilepticus mirrors that found in animal models of refractory status epilepticus and may promote self-sustaining seizures. Receptor subunit changes may provide additional targets for improved treatment.

Autoantibodies to Glutamate Receptor Antigens in Multiple Sclerosis and Rasmussen's Encephalitis

Background: Glutamate and its specific ionotropic receptors, including N-methyl-<smlcap>D</smlcap>-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, are supposed to play an important role in neurodegeneration as well as neuronal regeneration. Although autoantibodies (aab) to glutamate receptors (GluR) have been identified in several neurologic diseases, including paraneoplastic encephalitis and Rasmussen's encephalitis (RE) with an increasing prevalence, the presence and role of anti-GluR aab in multiple sclerosis (MS) have not been studied yet. Objectives and Methods: In this study, we tested the serum samples of 56 subjects, including patients with relapsing-remitting MS (n = 25), patients with RE (n = 8), and healthy donors (HD; n = 23), for anti-GluR aab by immunoblot analysis of a panel of recombinantly expressed GluR proteins, including GluN1, GluN2C, GluA3, GluK2, and GluD2. Results: aab were mainly found directed against GluN1 and, except for one aab positive to GluK2 in 1 MS patient and 2 HD controls positive for GluA3, no other anti-GluR aab were detected. In the sera of RE patients, no anti-GluR aab were found. In patients with MS, 8 of the 25 sera (32%) tested positive for GluN1. Compared to the HD (6/23; 26%), this difference was not statistically significant (p = 0.28). Conclusions: Our study showed that if anti-GluR aab were detectable in HD and MS patients, they were mainly directed against GluN1 (in particular to oligomeric protein complexes) and were not found in RE. Those antibodies may have low titers and low affinities and might be considered an immune epiphenomenon. Hence, further studies will have to clarify their potential role as a surrogate marker for the extent of neuronal destruction or regeneration, respectively.

Scavenging ROS dramatically increase NMDA receptor whole-cell currents in painted turtle cortical neurons.

Oxygen deprivation triggers excitotoxic cell death in mammal neurons through excessive calcium loading via over-activation of N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This does not occur in the western painted turtle, which overwinters for months without oxygen. Neurological damage is avoided through anoxia-mediated decreases in NMDA and AMPA receptor currents that are dependent upon a modest rise in intracellular Ca(2+) concentrations ([Ca(2+)]i) originating from mitochondria. Anoxia also blocks mitochondrial reactive oxygen species (ROS) generation, which is another potential signaling mechanism to regulate glutamate receptors. To assess the effects of decreased intracellular [ROS] on NMDA and AMPA receptor currents, we scavenged ROS with N-2-mercaptopropionylglycine (MPG) or N-acetylcysteine (NAC). Unlike anoxia, ROS scavengers increased NMDA receptor whole-cell currents by 100%, while hydrogen peroxide decreased currents. AMPA receptor currents and [Ca(2+)]i concentrations were unaffected by ROS manipulation. Because decreases in [ROS] increased NMDA receptor currents, we next asked whether mitochondrial Ca(2+) release prevents receptor potentiation during anoxia. Normoxic activation of mitochondrial ATP-sensitive potassium (mKATP) channels with diazoxide decreased NMDA receptor currents and was unaffected by subsequent ROS scavenging. Diazoxide application following ROS scavenging did not rescue scavenger-mediated increases in NMDA receptor currents. Fluorescent measurement of [Ca(2+)]i and ROS levels demonstrated that [Ca(2+)]i increases before ROS decreases. We conclude that decreases in ROS concentration are not linked to anoxia-mediated decreases in NMDA/AMPA receptor currents but are rather associated with an increase in NMDA receptor currents that is prevented during anoxia by mitochondrial Ca(2+) release.

Perampanel: What is its Place in the Management of Partial Onset Epilepsy?

IntroductionCurrent pathways for treatment of partial onset epilepsy are diverse and include 14 new antiepileptic drugs (AEDs) licensed for use as either monotherapy or adjunctive therapy. However, the impact of these new AEDs on the treatment of partial epilepsy has so far been disappointing and there persists a need for additional drugs. Recently, perampanel, a first-in-class AED was licensed as an adjunct for the management of refractory partial onset seizures with or without secondary generalization in patients 12 years and older. This review highlights the current management of partial epilepsy and analyses the published clinical and preclinical data of perampanel to consider its potential role in the treatment of partial epilepsy.MethodsA literature review of Embase, Medline and PubMed was conducted in April 2013 using the search terms ‘perampanel’ and ‘AMPA receptor antagonist/blocker’. Publications were included if they discussed perampanel in the context of preclinical or clinical epilepsy.ResultsPerampanel acts on the glutamate pathway. It is a novel highly selective non-competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist. This is a previously untargeted post-synaptic glutamate receptor. It is responsible for mediating rapid trans-synaptic signal transduction and hence believed to play a major role in seizure propagation. The three pivotal placebo-controlled trials of adjunctive perampanel demonstrated that the effective dosing range is 4–12 mg/day. The drug can be prescribed once daily, and its adverse effect profile is minimal with dizziness, fatigue, headache, and somnolence being the most commonly reported.ConclusionsPerampanel is a welcome addition as it represents an alternative approach in the management of epilepsy with potential to have a significant impact on the prognosis of intractable epilepsy. However, it has only recently been licensed for clinical use in Europe, the USA, and Canada, and there are no data directly comparing it with other AEDs; hence, it remains far too early to ascertain its place in the treatment of patients with partial epilepsy.

Possible effect of perampanel on focal status epilepticus after generalized tonic–clonic status epilepticus

Since in refractory status epilepticus (SE), additional glutamate receptors such as alpha-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid (AMPA) and N-methyl-Daspartate (NMDA) receptors are built up in the synaptic membrane [1], perampanel, a novel noncompetitive AMPA-receptor antagonist, may be effective in this condition. During the treatment of refractory SE, usually a combination therapy of several antiepileptic drugs (AEDs) is established. Therefore, the drug, which has terminated the SE, cannot easily be identified. A possible effect of an AED on the termination of a SE may be supposed, when the termination of a SE is associated with the introduction of an AED in the therapy or an increased dose of an AED in combination with other changes in the antiepileptic medication at the same time [2]. Here we present a case where perampanel was the last AED introduced in the treatment of a focal SE before its termination 24 h later.

Antidepressant effects of AMPA and ketamine combination: role of hippocampal BDNF, synapsin, and mTOR

A number of preclinical and clinical studies suggest that ketamine, a glutamate N-methyl-D-aspartate receptor antagonist, has a rapid and lasting antidepressant effect when administered either acutely or chronically. It has been postulated that this effect is due to stimulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In this study, we tested whether AMPA alone has an antidepressant effect and if the combination of AMPA and ketamine provides added benefit in Wistar-Kyoto rats, a putative animal model of depression. Chronic AMPA treatment resulted in a dose-dependent antidepressant effect in both the forced swim test and sucrose preference test. Moreover, chronic administration (10-11 days) of combinations of AMPA and ketamine, at doses that were ineffective on their own, resulted in a significant antidepressant effect. The behavioral effects were associated with increases in hippocampal brain-derived neurotrophic factor, synapsin, and mammalian target of rapamycin. These findings are the first to provide evidence for an antidepressant effect of AMPA and suggest the usefulness of AMPA-ketamine combination in treatment of depression. Furthermore, these effects appear to be associated with increases in markers of hippocampal neurogenesis and synaptogenesis, suggesting a mechanism of their action.

Impaired motor learning attributed to altered AMPA receptor function in the cerebellum of rats with temporal lobe epilepsy: Ameliorating effects of Withania somnifera and withanolide A

The aim of this study was to investigate the effect of Withania somnifera (WS) extract, withanolide A (WA), and carbamazepine (CBZ) on cerebellar AMPA receptor function in pilocarpine-induced temporal lobe epilepsy (TLE). In the present study, motor learning deficit was studied by rotarod test, grid walk test, and narrow beam test. Motor learning was significantly impaired in rats with epilepsy. The treatment with WS and WA significantly reversed the motor learning deficit in rats with epilepsy when compared with control rats. There was an increase in glutamate content and IP3 content observed in rats with epilepsy which was reversed in WS- and WA-treated rats with epilepsy. alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor dysfunction was analyzed using radiolabeled AMPA receptor binding assay, AMPA receptor mRNA expression, and immunohistochemistry using anti-AMPA receptor antibody. Our results suggest that there was a decrease in Bmax, mRNA expression, and AMPA receptor expression indicating AMPA receptor dysfunction, which is suggested to have contributed to the motor learning deficit observed in rats with epilepsy. Moreover, treatment with WS and WA resulted in physiological expression of AMPA receptors. There was also alteration in GAD and GLAST expression which supplemented the increase in extracellular glutamate. The treatment with WS and WA reversed the GAD and GLAST expression. These findings suggest that WS and WA regulate AMPA receptor function in the cerebellum of rats with TLE, which has therapeutic application in epilepsy.

Pathogenesis of Abeta Oligomers in Synaptic Failure

The soluble Abeta oligomers in brain are highly correlated with memory related synaptic dysfunctions in Alzheimer's disease (AD). However, more recent studies implicate the involvement of Abeta dimers and trimers in memory related AD pathology. Apparently, Abeta oligomers can bind with cellular prion protein at the membrane receptors, forming annular amyloid pores and membrane ion channels to induce aberrant spine cytoskeletal changes. Hence synapse targeting of Abeta oligomers involves activation of many receptors such as N-Methyl-D-aspartate (NMDA), alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), nicotinic acetylcholine (nAChRs), p75 neurotrophin (p75NTR) following aberrant clustering of metabotropic glutamate receptors (mGluR5) leading to neuronal loss and LTP failure. In particular, NMDA and AMPA receptor activation by soluble amyloid oligomers involves calcium mediated mitochondrial dysfunction, decreased Ca((2+))/calmodulin-dependent protein kinase II (CaMKII) levels at the synapses accompanying dramatic loss of synaptic proteins such as postsynaptic density-95 (PSD-95), dynamin-1 and synaptophysin. This kind of receptor-Abeta oligomer interaction might eventually affect the neuronal membrane integrity by altering dielectric barrier, various synaptic proteins, spine morphology and density and P/Q calcium currents that might provoke a cascade of events leading to neuronal loss and memory failure. In this review, we try to explain in detail the various possible mechanisms that connect Abeta oligomers with synapse damage and memory failure.

Stimulation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor evokes mixed responses in nociceptive fibers of mouse glabrous skin

This study examined the contribution of AMPA receptors to peripheral nociception using teased plantar nerve attached to glabrous skin of male C57B/6 mice. Identified receptive fields were isolated using a plastic well. After measuring mechanical (MECH), heat and cold responses, serial 10X dilutions of AMPA ranging from 1 pM to 1 mM were pipetted into the well. Firing activity was collected over 2 min for each dilution. After a 2 min wash-out, MECH, heat, and cold responses were re-measured. A 50% increase or decrease in threshold or firing rate was considered significant.

Acute ketamine induces hippocampal synaptic depression and spatial memory impairment through dopamine D1/D5 receptors

Subanesthetic doses of ketamine have been reported to induce psychotic states that may mimic positive and negative symptoms as well as cognitive and memory deficits similar to those observed in schizophrenia. The cognitive and memory deficits are persistent, and their underlying cellular mechanisms remain unclear. We sought to investigate the roles of dopamine D1/D5 receptors and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in hippocampal synaptic transmission and spatial memory impairment induced by ketamine. We examined the effects of subanesthetic ketamine on hippocampal synaptic transmission in freely moving rats. Spatial memory was tested with the Morris water maze. Pretreatment with the D1/D5 receptors antagonist SCH23390 or the AMPA receptors endocytosis interfering peptide Tat-GluR23Y was conducted to examine their capacities to reverse ketamine-induced electrophysiological and behavioral alterations. A series of behavioral observations, including locomotion, prepulse inhibition, and social interaction, were also conducted after ketamine treatment. Ketamine induced synaptic depression lasting at least 4 h at hippocampal Schaffer collateral-CA1 synapses in freely moving rats and long-term spatial memory impairment. Both the effects were blocked by either SCH23390 or Tat-GluR23Y. Ketamine also elicited transient behavioral changes lasting less than 90 min, such as hyperlocomotion and prepulse inhibition deficits. These changes were ameliorated by SCH23390 but not by Tat-GluR23Y. Rats treated with ketamine showed social withdrawal that was also attenuated by either SCH23390 or Tat-GluR23Y. Our results indicate that hippocampal synaptic depression is involved in ketamine-induced memory impairment, and this is modulated by D1/D5 receptors activation and AMPA receptors endocytosis.

Development of perampanel in epilepsy

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors play a key role in mediating glutamatergic transmission in the cortex. Perampanel (2-[2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl] benzonitrile) is a potent, orally active, highly selective, non-competitive AMPA-type glutamate receptor antagonist, identified via a focused discovery program at Eisai Research Laboratories. Development of perampanel as adjunctive therapy for the treatment of partial-onset seizures was planned in keeping with regulatory guidance and guidelines on antiepileptic drug (AED) development. This is the first AED with a specific action on glutamate-mediated excitatory neurotransmission to show evidence of efficacy and tolerability in reducing treatment-refractory partial-onset seizures in Phase III clinical trials. Perampanel (Fycompa(®)) has been approved in the EU and the United States for adjunctive treatment of partial-onset seizures.

Safety and tolerability of perampanel: a review of clinical trial data

The Phase II and Phase III clinical development program of perampanel is providing a wealth of data on the safety and tolerability of this alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist as an adjuvant treatment for refractory partial-onset seizures. In Phase II dose-finding studies, perampanel was associated with an acceptable tolerability profile up to the maximum evaluated dose of 12 mg/day. Subsequent multinational, multicenter, randomized, double-blind, placebo-controlled Phase III registration studies further supported the tolerability of perampanel across the dose range 2-12 mg/day, with interim data from ongoing extension studies indicating that safety outcomes may be maintained over several years. An analysis of the pooled Phase III data indicated that the frequency of adverse events reported with perampanel generally increased in a dose-dependent manner, and the most common adverse events were dizziness and somnolence. Overall, perampanel has been associated with an acceptable and consistent safety profile that is maintained over long-term settings.

AMPAR trafficking in synapse maturation and plasticity.

Glutamate ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate most fast excitatory synaptic transmission in the central nervous system. The content and composition of AMPARs in postsynaptic membranes (which determine synaptic strength) are dependent on the regulated trafficking of AMPAR subunits in and out of the membranes. AMPAR trafficking is a key mechanism that drives nascent synapse development, and is the main determinant of both Hebbian and homeostatic plasticity in mature synapses. Hebbian plasticity seems to be the biological substrate of at least some forms of learning and memory; while homeostatic plasticity (also known as synaptic scaling) keeps neuronal circuits stable by maintaining changes within a physiological range. In this review, we examine recent findings that provide further understanding of the role of AMPAR trafficking in synapse maturation, Hebbian plasticity, and homeostatic plasticity.

Time-dependent modulation of AMPA receptor phosphorylation and mRNA expression of NMDA receptors and glial glutamate transporters in the rat hippocampus and cerebral cortex in a pilocarpine model of epilepsy

The pilocarpine model in rodents reproduces the main features of mesial temporal lobe epilepsy related to hippocampus sclerosis (MTLE-HS) in humans. It has been demonstrated in this model that the phosphorylation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR1 subunit is increased 1 h after pilocarpine treatment. Moreover, alterations in the levels of glutamate transporters have been associated with chronic epilepsy in humans. Despite these studies, the profile of these changes has not yet been addressed. We analyzed the protein content and phosphorylation profile of the AMPA receptor GluR1 subunit by western blotting. We also used quantitative real-time polymerase chain reaction to analyze the expression of glial glutamate transporters and the N-methyl-D-aspartate receptor NR1 subunit in the hippocampus (Hip) and cerebral cortex (Ctx) at different time points after pilocarpine-induced status epilepticus (Pilo-SE) in male adult Wistar rats. Biochemical analysis was performed in the Hip and Ctx at 1, 3, 12 h (acute period), 5 days (latent period), and 50 days (chronic period) after Pilo-SE. Key findings include an increase in the phosphorylation of GluR1-Ser(845) in the Ctx and GluR1-Ser(831) in the Hip at different times during the acute period, and a decrease in the total content of the GluR1 subunit in the Ctx in the latent period. There was a down-regulation of the mRNA expression and protein levels of EAAT1 and EAAT2, and a decrease of the NR1 mRNA expression, in the Ctx during the latent period. Notably, during the chronic period, the EAAT2 mRNA expression and protein levels decreased while the NR1 mRNA levels increased in the Hip. Taken together, our findings suggest a time- and structure-dependent imbalance of glutamatergic transmission in response to Pilo-SE, which might be associated with either epileptogenesis or the seizure threshold in MTLE-HS.

Novel Drug for Partial-Onset Seizures Approved

The Food and Drug Administration added another arrow to the quiver of epilepsy specialists by approving perampanel for the treatment of partial-onset seizures, primarily in adult patients with epilepsy. Perampanel, which will be marketed by Eisai Inc. under the brand name Fycompa, was the first antiepileptic drug (AED) to be submitted to the agency on the basis of an excitation mechanism rather than membrane inhibition or stabilization, according to Dr. Jacqueline French of New York University, who was an investigator in clinical studies of the drug. The AED is a highly selective, noncompetitive, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist. “Some people with epilepsy do not achieve satisfactory seizure control from treatments they are currently using,” said Dr. Russell Katz, director of the Division of Neurology Products in the FDA's Center for Drug Evaluation and Research. “It is important to have a variety of treatment options available for patients with epilepsy.” Three phase III trials of the drug have reported 28-day reductions in seizure frequency relative to placebo in patients who were taking one to three other AEDs. The drug's label will include a boxed warning about the risk of serious (and in some cases life-threatening) neuropsychiatric events that were recorded during clinical trials, including irritability, aggression, anger, anxiety, paranoia, euphoric mood, agitation, and mental status changes. The agency noted that health care professionals should “closely monitor patients during the titration period when higher doses are used.” The drug is not for use in children. It is already approved in the European Union.

Are Onconeural Antibodies a Clinical Phenomenology in Paraneoplastic Limbic Encephalitis?

Paraneoplastic neurological syndromes (PNSs) occur in patients with cancer and can cause clinical symptoms and signs of dysfunction of the nervous system that are not due to a local effect of the tumor or its metastases. Most of these clinical syndromes in adults are associated with lung cancer, especially small cell lung cancer (SCLC), lymphoma, and gynecological tumors. The finding of highly specific antibodies directed against onconeural antigens has revolutionized the diagnosis and promoted the understanding of these syndromes and led to the current hypothesis of an autoimmune pathophysiology. Accumulating data strongly suggested direct pathogenicity of these antibodies. The field of PNS has expanded rapidly in the past few years with the discovery of limbic encephalitis associated with glutamic acid decarboxylase (GAD) 65, the voltage (VGKC-gated potassium channel) complex, the methyl (N-NMDA-D-aspartate), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and gamma aminobutyric acid (GABA) (B) receptors, and so forth. Despite this, the clinical spectrum of these diseases has not yet been fully investigated. The clinical importance of these conditions lies in their frequent response to immunotherapies and, less commonly, their association with distinctive tumors. This review provides an overview on the pathogenesis and diagnosis of PNS, with emphasis on the role of antibodies in limbic encephalitis.

Role of nucleus accumbens glutamatergic plasticity in drug addiction

Substance dependence is characterized by a group of symptoms, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). These symptoms include tolerance, withdrawal, drug consumption for alleviating withdrawal, exaggerated consumption beyond original intention, failure to reduce drug consumption, expending a considerable amount of time obtaining or recovering from the substance’s effects, disregard of basic aspects of life (for example, family), and maintenance of drug consumption, despite facing adverse consequences. The nucleus accumbens (NAc) is a brain structure located in the basal forebrain of vertebrates, and it has been the target of addictive drugs. Different neurotransmitter systems at the level of the NAc circuitry have been linked to the different problems of drug addiction, like compulsive use and relapse. The glutamate system has been linked mainly to relapse after drug-seeking extinction. The dopamine system has been linked mainly to compulsive drug use. The glutamate homeostasis hypothesis centers around the dynamics of synaptic and extrasynaptic levels of glutamate, and their impact on circuitry from the prefrontal cortex (PFC) to the NAc. After repetitive drug use, deregulation of this homeostasis increases the release of glutamate from the PFC to the NAc during drug relapse. Glial cells also play a fundamental role in this hypothesis; glial cells shape the interactions between the PFC and the NAc by means of altering glutamate levels in synaptic and extrasynaptic spaces. On the other hand, cocaine self-administration and withdrawal increases the surface expression of subunit glutamate receptor 1 (GluA1) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors at the level of the NAc. Also, cocaine self-administration and withdrawal induce the formation of subunit glutamate receptor 2 (GluA2), lacking the Ca2+-permeable AMPA receptors (CP-AMPARs) at the level of the NAc. Antagonism of the CP-AMPARs reduces cravings. It is necessary to pursue further exploration of the AMPA receptor subunit composition and variations at the level of the NAc for a better understanding of glutamatergic plastic changes. It is known that cocaine and morphine are able to induce changes in dendritic spine morphology by modifying actin cycling. These changes include an initial increase in spine head diameter and increases in AMPA receptor expression, followed by a second stage of spine head diameter retraction and reduction of the AMPA receptors’ expression in spines. Besides glutamate and dopamine, other factors, like brain-derived neurotrophic factor (BDNF), can influence NAc activity and induce changes in dendritic spine density. BDNF also induces drug-related behaviors like self-administration and relapse. Neither apoptosis nor neurogenesis plays a relevant role in the neurobiological processes subjacent to cocaine addiction in adults (rodent or human). Different therapeutic drugs like N-acetylcysteine (NAC), modafinil, acamprosate, and topiramate have been tested in preclinical and/or clinical models for alleviating drug relapse. Moreover, these therapeutic drugs target the glutamatergic circuitry between the PFC and the NAc. NAC and acamprosate have shown inconsistent results in clinical trials. Modafinil and topiramate have shown some success, but more clinical trials are necessary. Based on the current review findings, it could be recommendable to explore therapeutic approaches that include synergism between different drugs and neurotransmitter systems. The discrepancy in the results of some therapeutic drugs between preclinical versus clinical trials for alleviating relapse or drug dependence could be linked to the scarce exploration of preclinical models that mimic polydrug abuse patterns, for example, cocaine plus alcohol. At the clinical level, the pattern of polydrug consumption is a phenomenon of considerable frequency. Finally, as a complement at the end, an updated summary is included about the role of glutamate in other neuropsychiatric disorders (for example, mood disorders, schizophrenia, and others).

Inhibitory Effects of Acorn Extract on Glutamate-Induced Calcium Signaling in Cultured Rat Hippocampal Neurons

Various effects of acorn extract have been reported including antioxidant activity, cytotoxicity against cancer cells, and the levels of acetylcholine and its related enzyme activities in the dementia mouse models. However, it is unclear whether acorn extract inhibits glutamate-induced calcium signaling in hippocampal neurons. This study was an investigation into the effect of acorn extract on intracellular free Ca concentrations ([Ca]) in cultured rat hippocampal neurons using fura-2-based digital calcium imaging and photometry. Hippocampal neurons were used between 10 and 14 d in culture from embryonic day-18 rats. Treatment with acorn extract (1 µg/mL to 1 mg/mL) for 30 min inhibited glutamate (100 µM)-induced [Ca] increases in a dose-dependent manner (IC=46.9 µg/mL). After depletion of intracellular Ca stores by treatment with the inhibitor endoplasmic reticulum Ca-ATPase, thapsigargin (1 µM), treatment with acorn extract (50 µg/mL) for 30 min decreased the subsequent glutamate-induced [Ca] increases. Acorn extract significantly inhibited (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (30 µM)-induced [Ca] increases. In addition, acorn extract inhibited the AMPA-induced [Ca] responses in the presence of 1 µM nimodipine. Acorn extract also significantly inhibited N-methyl-D-aspartate (100 µM)-induced [Ca] increases. Acorn extract significantly inhibited 50 mM KCl -induced [Ca] increases. Acorn extract significantly inhibited (S)-3,5-dihydroxyphenylglycine-induced [Ca] responses. Moreover, acorn extract almost completely blocked synaptically mediated [Ca] spikes induced by decreasing extracellular Mg concentration to 0.1 mM. These results suggest that acorn extract inhibits synaptically induced frequent [Ca] spikes through multiple pathways such as ionotropic glutamate receptors, voltage-gated Ca channels and metabotropic glutamate receptors in cultured rat hippocampal neurons.

Implementing the cellular mechanisms of synaptic transmission in a neural mass model of the thalamo-cortical circuitry

A novel direction to existing neural mass modeling technique is proposed where the commonly used “alpha function” for representing synaptic transmission is replaced by a kinetic framework of neurotransmitter and receptor dynamics. The aim is to underpin neuro-transmission dynamics associated with abnormal brain rhythms commonly observed in neurological and psychiatric disorders. An existing thalamocortical neural mass model is modified by using the kinetic framework for modeling synaptic transmission mediated by glutamatergic and GABA (gamma-aminobutyric-acid)-ergic receptors. The model output is compared qualitatively with existing literature on in vitro experimental studies of ferret thalamic slices, as well as on single-neuron-level model based studies of neuro-receptor and transmitter dynamics in the thalamocortical tissue. The results are consistent with these studies: the activation of ligand-gated GABA receptors is essential for generation of spindle waves in the model, while blocking this pathway leads to low-frequency synchronized oscillations such as observed in slow-wave sleep; the frequency of spindle oscillations increase with increased levels of post-synaptic membrane conductance for AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic-acid) receptors, and blocking this pathway effects a quiescent model output. In terms of computational efficiency, the simulation time is improved by a factor of 10 compared to a similar neural mass model based on alpha functions. This implies a dramatic improvement in computational resources for large-scale network simulation using this model. Thus, the model provides a platform for correlating high-level brain oscillatory activity with low-level synaptic attributes, and makes a significant contribution toward advancements in current neural mass modeling paradigm as a potential computational tool to better the understanding of brain oscillations in sickness and in health.

TMHS Is an Integral Component of the Mechanotransduction Machinery of Cochlear Hair Cells

Hair cells are mechanosensors for the perception of sound, acceleration, and fluid motion. Mechanotransduction channels in hair cells are gated by tip links, which connect the stereocilia of a hair cell in the direction of their mechanical sensitivity. The molecular constituents of the mechanotransduction channels of hair cells are not known. Here, we show that mechanotransduction is impaired in mice lacking the tetraspan TMHS. TMHS binds to the tip-link component PCDH15 and regulates tip-link assembly, a process that is disrupted by deafness-causing Tmhs mutations. TMHS also regulates transducer channel conductance and is required for fast channel adaptation. TMHS therefore resembles other ion channel regulatory subunits such as the transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor regulatory proteins (TARPs) of AMPA receptors that facilitate channel transport and regulate the properties of pore-forming channel subunits. We conclude that TMHS is an integral component of the hair cell's mechanotransduction machinery that functionally couples PCDH15 to the transduction channel.