non-NMDA Receptors Research Articles

Possible Participation of Ionotropic Glutamate Receptors and l-Arginine-Nitric Oxide-Cyclic Guanosine Monophosphate-ATP-Sensitive K+ Channel Pathway in the Antinociceptive Activity of Cardamonin in Acute Pain Animal Models.

The perception of pain caused by inflammation serves as a warning sign to avoid further injury. The generation and transmission of pain impulses involves various pathways and receptors. Cardamonin isolated from Boesenbergia rotunda (L.) Mansf. has been reported to exert antinociceptive effects in thermal and mechanical pain models; however, the precise mechanism has yet to be examined. The present study investigated the possible mechanisms involved in the antinociceptive activity of cardamonin on protein kinase C, N-methyl-d-aspartate (NMDA) and non-NMDA glutamate receptors, l-arginine/cyclic guanosine monophosphate (cGMP) mechanism, as well as the ATP-sensitive potassium (K+) channel. Cardamonin was administered to the animals intra-peritoneally. Present findings showed that cardamonin significantly inhibited pain elicited by intraplantar injection of phorbol 12-myristate 13-acetate (PMA, a protein kinase C activator) with calculated mean ED50 of 2.0 mg/kg (0.9–4.5 mg/kg). The study presented that pre-treatment with MK-801 (NMDA receptor antagonist) and NBQX (non-NMDA receptor antagonist) significantly modulates the antinociceptive activity of cardamonin at 3 mg/kg when tested with glutamate-induced paw licking test. Pre-treatment with l-arginine (a nitric oxide precursor), ODQ (selective inhibitor of soluble guanylyl cyclase) and glibenclamide (ATP-sensitive K+ channel inhibitor) significantly enhanced the antinociception produced by cardamonin. In conclusion, the present findings showed that the antinociceptive activity of cardamonin might involve the modulation of PKC activity, NMDA and non-NMDA glutamate receptors, l-arginine/nitric oxide/cGMP pathway and ATP-sensitive K+ channel.

The Redox Biology of Excitotoxic Processes: The NMDA Receptor, TOPA Quinone, and the Oxidative Liberation of Intracellular Zinc.

This special issue of Frontiers in Neuroscience-Neurodegeneration celebrates the 50th anniversary of John Olney’s seminal work introducing the concept of excitotoxicity as a mechanism for neuronal cell death. Since that time, fundamental research on the pathophysiological activation of glutamate receptors has played a central role in our understanding of excitotoxic cellular signaling pathways, leading to the discovery of many potential therapeutic targets in the treatment of acute or chronic/progressive neurodegenerative disorders. Importantly, excitotoxic signaling processes have been found repeatedly to be closely intertwined with oxidative cellular cascades. With this in mind, this review looks back at long-standing collaborative efforts by the authors linking cellular redox status and glutamate neurotoxicity, focusing first on the discovery of the redox modulatory site of the N-methyl-D-aspartate (NMDA) receptor, followed by the study of the oxidative conversion of 3,4-dihydroxyphenylalanine (DOPA) to the non-NMDA receptor agonist and neurotoxin 2,4,5-trihydroxyphenylalanine (TOPA) quinone. Finally, we summarize our work linking oxidative injury to the liberation of zinc from intracellular metal binding proteins, leading to the uncovering of a signaling mechanism connecting excitotoxicity with zinc-activated cell death-signaling cascades.

The cyanobacterial neurotoxin \u03b2-N-methylamino-l-alanine (BMAA) targets the olfactory bulb region

Olfactory dysfunction is implicated in neurodegenerative disorders and typically manifests years before other symptoms. The cyanobacterial neurotoxin β-N-methylamino-l-alanine (BMAA) is suggested as a risk factor for neurodegenerative disease. Detection of BMAA in air filters has increased the concern that aerosolization may lead to human BMAA exposure through the air. The aim of this study was to determine if BMAA targets the olfactory system. Autoradiographic imaging showed a distinct localization of radioactivity in the right olfactory mucosa and bulb following a unilateral intranasal instillation of 3H-BMAA (0.018 µg) in mice, demonstrating a direct transfer of BMAA via the olfactory pathways to the brain circumventing the blood–brain barrier, which was confirmed by liquid scintillation. Treatment of mouse primary olfactory bulb cells with 100 µM BMAA for 24 h caused a disruption of the neurite network, formation of dendritic varicosities and reduced cell viability. The NMDA receptor antagonist MK-801 and the metabotropic glutamate receptor antagonist MCPG protected against the BMAA-induced alterations, demonstrating the importance of glutamatergic mechanisms. The ionotropic non-NMDA receptor antagonist CNQX prevented the BMAA-induced decrease of cell viability in mixed cultures containing both neuronal and glial cells, but not in cultures with neurons only, suggesting a role of neuron–glial interactions and glial AMPA receptors in the BMAA-induced toxicity. The results show that the olfactory region may be a target for BMAA following inhalation exposure. Further studies on the relations between environmental olfactory toxicants and neurodegenerative disorders are warranted.

IL-1\u03b2 induces rod degeneration through the disruption of retinal glutamate homeostasis

BackgroundAge-related macular degeneration is characterized by the accumulation of subretinal macrophages and the degeneration of cones, but mainly of rods. We have previously shown that Mononuclear Phagocytes-derived IL-1β induces rod photoreceptor cell death during experimental subretinal inflammation and in retinal explants exposed to IL-1β but the mechanism is unknown.MethodsRetinal explants were culture in the presence of human monocytes or IL-1β and photoreceptor cell survival was analyzed by TUNEL labeling. Glutamate concentration and transcription levels of gene involved in the homeostasis of glutamate were analyzed in cell fractions of explant cultured or not in the presence of IL-1β. Glutamate receptor antagonists were evaluated for their ability to reduce photoreceptor cell death in the presence of IL1-β or monocytes.ResultsWe here show that IL-1β does not induce death in isolated photoreceptors, suggesting an indirect effect. We demonstrate that IL-1β leads to glutamate-induced rod photoreceptor cell death as it increases the extracellular glutamate concentrations in the retina through the inhibition of its conversion to glutamine in Müller cells, increased release from Müller cells, and diminished reuptake. The inhibition of non-NMDA receptors completely and efficiently prevented rod apoptosis in retinal explants cultured in the presence of IL-1β or, more importantly, in vivo, in a model of subretinal inflammation.ConclusionsOur study emphasizes the importance of inflammation in the deregulation of glutamate homeostasis and provides a comprehensive mechanism of action for IL-1β-induced rod degeneration.

Ionotropic Glutamate Receptors and Their Implications in Cancer and Therapeutics

Glutamine, being excitative in nature, is a necessary element for physiological and pathological processes alike, has made glutamate receptors a vital space of studies and analysis. The metabotropic (mGluR) and ionotropic (iGluR) receptors have been employed in treating a range of cancers and commonest ones like carcinoma of Lung, Breast, Prostrate, oral cancer in which mGluR 1-8 (group I,II,III) are accountable whereas (iGluR) ionotropic glutamate receptors which cover NMDA and NON NMDA receptors, have an affect a variety of cancers otherwise. NMDARs are further divided into subunits and influence mTOR signaling pathway significantly. Hence, anti-cancer agents specific to NMDARs are indicated in such scenarios like that of Memantine, Ifenprodil or Diclozipine. Some subunits; AMPARs and KARs, endure glutamine to Arginine(Q/R) site specific ribonucleic acid (RNA) editing inflicting changes in Ca permeability as well as its action that is seen to be altered in tumors. Therefore, their antagonists would prove functional. Since AMPAR, KARs have a giant role in neural development and processes, they have chiefly been detected in brain tumors not that their contribution in further cancers can be neglected. Delta or orphan receptors are primarily classified owing to sequence homology. In contrast to the rest of the iGluRs, these cannot be activated by any other receptors (AMPA, NMDA, KAR). Tumors that have a noteworthy contribution from either of the above mentioned receptors, in their progression, invasion and activity, are detailed individually and therefore the effect of metabotropic and ionotropic glutamate receptors have been pointed out owing to their remedial contribution like that of receptor antagonists, Riluzole. A good deal of analysis has to be done and this review highlights the relation of a range of sub-units to the cancer and anti-cancer agents as curatives for future applications and investigations. Some have conjointly seen application as markers for prognosis. Hence, the glutamate receptors have additionally been associated with an array of other cancers than just neuronal disorders and/or cancers.

Involvement of NMDA receptors in tremor expression in Aspa/Hcn1 double-knockout rats.

We recently demonstrated that aspartoacylase (Aspa) and hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (Hcn1) genes were causative of essential tremor (ET) in rats. This finding was obtained using Aspaem34Kyo/Hcn1A354V double-mutant rats, but they were bred on a heterogeneous genetic background of two strains, F344 and WTC. Here, we developed an Aspaem34Kyo/Hcn1em1Kyo double-knockout rat strain with a homogenous F344 genetic background and studied the ability of glutamate receptor antagonists to suppress ET. The F344-Aspa/Hcn1 double-knockout rats exhibited spontaneous, intense body tremor equivalent to that in the double-mutant rats. N-acetyl-aspartate (NAA), a substrate of ASPA, showed accumulation in all brain regions and in the spinal cord. However, N-acetyl-aspartyl-glutamate (NAAG), which is derived from NAA and interacts with glutamatergic receptors, was decreased in the medulla oblongata of the double-knockout rats. The tremor was suppressed by 3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid, an N-methyl-D-aspartate (NMDA) receptor antagonist, in F344-Aspa/Hcn1 double-knockout rats. The non-NMDA glutamate receptor antagonist NBQX weakly inhibited the tremor, while the metabotropic glutamate receptor antagonist LY341495 showed no effect. In addition, both NR2B subunit-specific (Ro 25-6981) and NR2C/NR2D subunit-specific (cis-piperidine dicarboxylic acid) NMDA receptor antagonists suppressed the tremor. These data indicated that the pathogenesis of tremor in Aspa/Hcn1 double-knockout rats involved ionotropic glutamate receptors, particularly NMDA receptors.

Two distinct electrophysiological mechanisms underlie extensive depolarization elicited by 2,4 diaminobutyric acid in leech Retzius neurons

Recent studies suggest that 2,4-DABA, a neurotoxic excitatory amino acid present in virtually all environments, but predominantly in aquatic ecosystems may be a risk factor for development of neurodegenerative diseases in animals and humans. Despite its neurotoxicity and potential environmental importance, mechanisms underlying the excitatory and putative excitotoxic action of 2,4-DABA in neurons are still unexplored. We previously reported on extensive two-stage membrane depolarization and functional disturbances in leech Retzius neurons induced by 2,4-DABA. Current study presents the first detailed look into the electrophysiological processes leading to this depolarization. Intracellular recordings were performed on Retzius neurons of the leech Haemopis sanguisuga using glass microelectrodes and input membrane resistance (IMR) was measured by injecting hyperpolarizing current pulses through these electrodes. Results show that the excitatory effect 2,4-DABA elicits on neurons’ membrane potential is dependent on sodium ions. Depolarizing effect of 5·10−3 mol/L 2,4-DABA in sodium-free solution was significantly diminished by 91% reducing it to 3.26 ± 0.62 mV and its two-stage nature was abrogated. In addition to being sodium-dependent, the depolarization of membrane potential induced by this amino acid is coupled with an increase of membrane permeability, as 2,4-DABA decreases IMR by 8.27 ± 1.47 MΩ (67.60%). Since present results highlight the role of sodium ions, we investigated the role of two putative sodium-dependent mechanisms in 2,4-DABA-induced excitatory effect – activation of ionotropic glutamate receptors and the electrogenic transporter for neutral amino acids. Excitatory effect of 5·10−3 mol/L 2,4-DABA was partially blocked by 10-5 mol/L 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) a non-NMDA receptor antagonist as the first stage of membrane depolarization was significantly reduced by 2.59 ± 0.98 mV (40%), whilst second stage remained unaltered. Moreover, involvement of the sodium-dependent transport system for neutral amino acids was investigated by equimolar co-application of 5·10−3 mol/L 2,4-DABA and L-alanine, a competitive inhibitor of this transporter. Although L-alanine exhibited no effect on the first stage of membrane depolarization elicited by 2,4-DABA, it substantially reduced the second stage (the overall membrane depolarization) from 39.63 ± 2.22 mV to 16.28 ± 2.58 mV, by 58.92%. We therefore propose that the electrophysiological effect of 2,4-DABA on Retzius neurons is mediated by two distinct mechanisms, i.e. by activation of ionotropic glutamate receptor that initiates the first stage of membrane depolarization followed by the stimulation of an electrogenic sodium-dependent neutral amino acid transporter, leading to additional influx of positive charge into the cell and the second stage of depolarization.

Involvement of glutamatergic mechanisms in the median preoptic nucleus in the dipsogenic response induced by angiotensinergic activation of the subfornical organ in rats.

Experiments were done to investigate the role of glutamatergic systems in the median preoptic nucleus (MnPO) in the water ingestion induced by administration of angiotensin II (ANG II) in the subfornical organ (SFO) in the awake rat. Microdialysis methods were utilized to quantify the extracellular content of glutamate (Glu) in the region of MnPO. Microinjection of ANG II (10-10M) into the SFO significantly increased the release of Glu in the MnPO in the rats under the condition that water is available for drinking and the rats under the condition that water is not available for drinking. The amount of initial maximal increases in the Glu levels elicited by the ANG II injection was quite similar in drinking and non-drinking rats, whereas the duration of the response was much longer in non-drinking than in drinking rats. The amount of water ingestion in 20min immediately after the ANG II injection was significantly enhanced by previous injections of N-methyl-D-aspartate (NMDA, 10μM) into the MnPO, while the ANG II-induced water ingestion was attenuated by pretreatment with the NMDA antagonist dizocilpine (MK-801, 10μM). The amount of water intake elicited by the ANG II injection into the SFO was enhanced by previous injections of either the non-NMDA agonist kainic acid (KA, 50μM) or quisqualic acid (QA, 50μM) into the MnPO. On the contrary, the ANG II-induced drinking response was diminished by pretreatment with the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10μM) in the MnPO. Each injection of NMDA, KA, and QA into the MnPO produced drinking behavior. These results imply that the glutamatergic neural pathways to the MnPO may transmit the information for eliciting drinking in response to ANG II acting at the SFO. Our data further provide evidence that the ANG II-induced dipsogenic response may be mediated through both NMDA and non-NMDA glutamatergic receptor mechanisms in the MnPO.

Neonatal ethanol exposure triggers apoptosis in the murine retrosplenial cortex: Role of inhibition of NMDA receptor-driven action potential firing

Exposure to ethanol during the last trimester equivalent of human pregnancy causes apoptotic neurodegeneration in the developing brain, an effect that is thought to be mediated, in part, by inhibition of NMDA receptors. However, NMDA receptors can rapidly adapt to the acute effects of ethanol and are ethanol resistant in some populations of developing neurons. Here, we characterized the effect of ethanol on NMDA and non-NMDA receptor-mediated synaptic transmission in the retrosplenial cortex (RSC), a brain region involved in the integration of different modalities of spatial information that is among the most sensitive regions to ethanol-induced neurodegeneration. A single 4-h exposure to ethanol vapor of 7-day-old transgenic mice that express the Venus fluorescent protein in interneurons triggered extensive apoptosis in the RSC. Slice electrophysiological recordings showed that bath-applied ethanol inhibits NMDA and non-NMDA receptor excitatory postsynaptic currents (EPSCs) in pyramidal neurons and interneurons; however, we found no evidence of acute tolerance development to this effect after the 4-h in-vivo ethanol vapor exposure. Acute bath application of ethanol reduced action potential firing evoked by synaptic stimulation to a greater extent in pyramidal neurons than interneurons. Submaximal inhibition of NMDA EPSCs, but not non-NMDA EPSCs, mimicked the acute effect of ethanol on synaptically-evoked action potential firing. These findings indicate that partial inhibition of NMDA receptors by ethanol has sizable effects on the excitability of glutamatergic and GABAergic neurons in the developing RSC, and suggest that positive allosteric modulators of these receptors could ameliorate ethanol intoxication-induced neurodegeneration during late stages of fetal development.

Serum-deprived differentiated neuroblastoma F-11 cells express functional dorsal root ganglion neuron properties.

The isolation and culture of dorsal root ganglion (DRG) neurons cause adaptive changes in the expression and regulation of ion channels, with consequences on neuronal excitability. Considering that not all neurons survive the isolation and that DRG neurons are heterogeneous, it is difficult to find the cellular subtype of interest. For this reason, researchers opt for DRG-derived immortal cell lines to investigate endogenous properties. The F-11 cell line is a hybridoma of embryonic rat DRG neurons fused with the mouse neuroblastoma line N18TG2. In the proliferative condition, F-11 cells do not display a gene expression profile correspondent with specific subclasses of sensory neurons, but the most significant differences when compared with DRGs are the reduction of voltage-gated sodium, potassium and calcium channels, and the small amounts of TRPV1 transcripts. To investigate if functional properties of mature F-11 cells showed more similarities with those of isolated DRG neurons, we differentiated them by serum deprivation. Potassium and sodium currents significantly increased with differentiation, and biophysical properties of tetrodotoxin (TTX)-sensitive currents were similar to those characterized in small DRG neurons. The analysis of the voltage-dependence of calcium currents demonstrated the lack of low threshold activated components. The exclusive expression of high threshold activated Ca2+ currents and of TTX-sensitive Na+ currents correlated with the generation of a regular tonic electrical activity, which was recorded in the majority of the cells (80%) and was closely related to the activity of afferent TTX-sensitive A fibers of the proximal urethra and the bladder. Responses to capsaicin and substance P were also recorded in ~20% and ~80% of cells, respectively. The percentage of cells responsive to acetylcholine was consistent with the percentage referred for rat DRG primary neurons and cell electrical activity was modified by activation of non-NMDA receptors as for embryonic DRG neurons. These properties and the algesic profile (responses to pH5 and sensitivity to both ATP and capsaicin), proposed in literature to define a sub-classification of acutely dissociated rat DRG neurons, suggest that differentiated F-11 cells express receptors and ion channels that are also present in sensory neurons.

A Brief Ischemic Postconditioning Protects Against Amyloid-β Peptide Neurotoxicity by Downregulating MLK3-MKK3/6-P38MAPK Signal in Rat Hippocampus.

Oligomeric amyloid-β peptide (Aβ) is associated with dysfunctional neuronal networks and neuronal loss in the development of Alzheimer's disease (AD). Ischemic postconditioning protects against post-ischemic excitotoxicity, oxidative stress, and inflammatory process that have also been implicated in the pathogenesis of AD. Evaluating the roles of ischemic postconditioning in oligomeric Aβ-induced neurotoxicity and underlying signal events may provide potential strategy for medical therapy in AD. The aim of the present study was to explore whether and how a brief ischemic postconditioning protects against Aβ neurotoxicity in rat hippocampus. Oligomeric Aβ25-35 (20 nmol/rat) or Aβ1-42 (5 nmol/rat) was infused by intracerebroventricular injection in adult male Sprague-Dawley rats. Ischemic postconditioning, a brief episode of global brain ischemia (3 min), was conducted at 1, 3, or 7 days after Aβ treatment, respectively. A brief ischemic postconditioning reduced neuronal loss and inhibited the activation of MLK3, MKK3/6, and P38MAPKs in rat hippocampal CA1 and CA3 subfields after Aβ oligomer infusion. An N-methyl-D-aspartate (NMDA) receptor antagonist amantadine, but not non-NMDA receptor antagonist CNQX, reversed the MLK3-MKK3/6-P38MAPK signal events and beneficial effect of ischemic postconditioning on neuronal survival. Such reversion was also realized by NVP-AAM077, a GluN2A-subunit-selective NMDA receptor antagonist. Moreover, posttreatment with low doses of NMDA (5 nmol-40 nmol/rat) suppressed the Aβ-induced P38MAPK signaling and imitated the neuroprotection of ischemic postconditioning against Aβ neurotoxicity. Ischemic postconditioning provides neuroprotection against Aβ neurotoxicity by moderate upregulation of NMDA receptor signaling, especially GluN2A-containing NMDA receptor pathway, and thereafter downregulation of MLK3-MKK3/6-P38MAPK signal events.

Guanosine and GMP increase the number of granular cerebellar neurons in culture: dependence on adenosine A2A and ionotropic glutamate receptors.

The guanine-based purines (GBPs) have essential extracellular functions such as modulation of glutamatergic transmission and trophic effects on neurons and astrocytes. We previously showed that GBPs, such as guanosine-5'-monophosphate (GMP) or guanosine (GUO), promote the reorganization of extracellular matrix proteins in astrocytes, and increase the number of neurons in a neuron-astrocyte co-culture protocol. To delineate the molecular basis underlying these effects, we isolated cerebellar neurons in culture and treated them with a conditioned medium derived from astrocytes previously exposed to GUO or GMP (GBPs-ACM) or, directly, with GUO or GMP. Agreeing with the previous studies, there was an increase in the number of β-tubulin III-positive neurons in both conditions, compared with controls. Interestingly, the increase in the number of neurons in the neuronal cultures treated directly with GUO or GMP was more prominent, suggesting a direct interaction of GBPs on cerebellar neurons. To investigate this issue, we assessed the role of adenosine and glutamate receptors and related intracellular signaling pathways after GUO or GMP treatment. We found an involvement of A2A adenosine receptors, ionotropic glutamate N-methyl-D-aspartate (NMDA), and non-NMDA receptors in the increased number of cerebellar neurons. The signaling pathways extracellular-regulated kinase (ERK), calcium-calmodulin-dependent kinase-II (CaMKII), protein kinase C (PKC), phosphatidilinositol-3'-kinase (PI3-K), and protein kinase A (PKA) are also potentially involved with GMP and GUO effect. Such results suggest that GMP and GUO, and molecules released in GBPs-ACM promote the survival or maturation of primary cerebellar neurons or both via interaction with adenosine and glutamate receptors.

Guanosine Prevents against Glutamatergic Excitotoxicity in C. elegans

Glutamatergic neurotransmission is present in most mammalian excitatory synapses and plays a key role in central nervous system homeostasis. When over-activated, it can induce excitotoxicity, which is present in several neuropathologies. The nucleoside guanosine (GUO) is a guanine-based purine known to have neuroprotective effects by modulating glutamatergic system during glutamate excitotoxicity in mammals. However, GUO action in Caenorhabditis elegans, as well as on C. elegans glutamatergic excitotoxicity model, is not known. The GUO effects on behavioral parameters in Wild Type (WT) and knockouts worms for glutamate transporters (GLT-3, GLT-1), glutamate vesicular transporter (EAT-4), and NMDA and non-NMDA receptors were used to evaluate the GUO modulatory effects. The GUO tested concentrations did not alter the animals' development, but GUO reduced pharyngeal pumps in WT animals in a dose-dependent manner. The same effect was observed in pharyngeal pumps, when the animals were treated with 4 mM of GUO in glr-1, nmr-1 and eat-4, but not in glt-3 and glt-3;glt-1 knockouts. The double mutant glt-3; glt-1 for GluTs had decreased body bends and an increased number of reversions. This effect was reverted after treatment with GUO. Furthermore, GUO did not alter the sensory response in worms with altered glutamatergic signaling. Thus, GUO seems to modulate the worm's glutamatergic system in situations of exacerbated glutamatergic signaling, which are represented by knockout strains to glutamate transporters. However, in WT animals, GUO appears to reinforce glutamatergic signaling in specific neurons. Our findings indicate that C. elegans strains are useful models to study new compounds that could be used in glutamate-associated neurodegenerative diseases.

The Effects of NMDA Receptor Blockade on Sensory-Evoked Responses in Superficial Layers of the Rat Barrel Cortex.

Transmission of excitation from L4 to L2/3 is a part of a canonical circuit of cortical sensory signal processing. While synapses from L4 to L2/3 are mediated by both AMPA and NMDA glutamate receptors, previous studies suggested that sensory-evoked excitation of neurons in supragranular layers is almost entirely mediated by NMDA receptors. Here, we readdressed this question using extracellular recordings of sensory-evoked potentials (SEPs) and multiple unit activity (MUA) in the rat barrel cortex. We found that blockade of NMDA receptors using the selective antagonist dAPV profoundly inhibited the late part of L2/3 SEP, the associated sink, and MUA response but did not affect its initial part. Our results indicate that both non-NMDA and NMDA receptors are involved in sensory signal transmission from L4 to L2/3. While non-NMDA receptors mediate fast transmission of sensory signals, NMDA-Rs are importantly involved in the generation of the late phase of the sensory-evoked response in supragranular layers.

Neurosteroid Actions in Memory and Neurologic/Neuropsychiatric Disorders.

Memory dysfunction is a symptomatic feature of many neurologic and neuropsychiatric disorders; however, the basic underlying mechanisms of memory and altered states of circuitry function associated with disorders of memory remain a vast unexplored territory. The initial discovery of endogenous neurosteroids triggered a quest to elucidate their role as neuromodulators in normal and diseased brain function. In this review, based on the perspective of our own research, the advances leading to the discovery of positive and negative neurosteroid allosteric modulators of GABA type-A (GABAA), NMDA, and non-NMDA type glutamate receptors are brought together in a historical and conceptual framework. We extend the analysis toward a state-of-the art view of how neurosteroid modulation of neural circuitry function may affect memory and memory deficits. By aggregating the results from multiple laboratories using both animal models for disease and human clinical research on neuropsychiatric and age-related neurodegenerative disorders, elements of a circuitry level view begins to emerge. Lastly, the effects of both endogenously active and exogenously administered neurosteroids on neural networks across the life span of women and men point to a possible underlying pharmacological connectome by which these neuromodulators might act to modulate memory across diverse altered states of mind.

Performance of the trial-unique, delayed non-matching-to-location (TUNL) task depends on AMPA/Kainate, but not NMDA, ionotropic glutamate receptors in the rat posterior parietal cortex.

Working memory (WM), the capacity for short-term storage and manipulation of small quantities of information, depends on fronto-parietal circuits. However, the function of the posterior parietal cortex (PPC) in WM has gone relatively understudied in rodents. Recent evidence calls into question whether the PPC is necessary for all forms of WM. Thus, the present experiment examined the role of the rat PPC in the Trial-Unique Non-matching-to-Location (TUNL) task, a touchscreen-based visuospatial WM task that relies on the rat medial prefrontal cortex (mPFC). Temporary inactivation of the PPC caused by bilateral infusions of muscimol and baclofen significantly impaired accuracy and increased the number of correction trials performed, indicating that the PPC is necessary for performance of TUNL. Additionally, we investigated the effects of blocking NMDA or non-NMDA parietal ionotropic glutamate receptors on TUNL and found that, in contrast to the prefrontal cortex, NMDA receptors in the PPC are not necessary for TUNL performance, whereas blockade of AMPA/Kainate receptors significantly impaired accuracy. These results indicate that performance of the TUNL task depends on the PPC but that NMDA receptor signaling within this brain area is not necessary for intact performance.

Comparison of Postoperative Analgesia Following Epidural Bupivacaine and Epidural Bupivacaine with Verapamil in Orthopaedic Lower Limb Surgeries

Comparison of Postoperative Analgesia Following Epidural Bupivacaine and Epidural Bupivacaine with Verapamil in Orthopaedic Lower Limb Surgeries

Inhibitory mechanisms shaping delay-tuned combination-sensitivity in the auditory cortex and thalamus of the mustached bat

Delay-tuned auditory neurons of the mustached bat show facilitative responses to a combination of signal elements of a biosonar pulse-echo pair with a specific echo delay. The subcollicular nuclei produce latency-constant phasic on-responding neurons, and the inferior colliculus produces delay-tuned combination-sensitive neurons, designated “FM-FM” neurons. The combination-sensitivity is a facilitated response to the coincidence of the excitatory rebound following glycinergic inhibition to the pulse (1st harmonic) and the short-latency response to the echo (2nd–4th harmonics). The facilitative response of thalamic FM-FM neurons is mediated by glutamate receptors (NMDA and non-NMDA receptors). Different from collicular FM-FM neurons, thalamic ones respond more selectively to pulse-echo pairs than individual signal elements. A number of differences in response properties between collicular and thalamic or cortical FM-FM neurons have been reported. However, differences between thalamic and cortical FM-FM neurons have remained to be studied. Here, we report that GABAergic inhibition controls the duration of burst of spikes of facilitative responses of thalamic FM-FM neurons and sharpens the delay tuning of cortical ones. That is, intra-cortical inhibition sharpens the delay tuning of cortical FM-FM neurons that is potentially broad because of divergent/convergent thalamo-cortical projections. Compared with thalamic neurons, cortical ones tend to show sharper delay tuning, longer response duration, and larger facilitation index. However, those differences are statistically insignificant.

Central inspiratory activity rhythmically activates synaptic currents of airway vagal preganglionic neurons in neonatal rats

The airway vagal preganglionic neurons (AVPNs) in the external formation of the nucleus ambiguus (eNA) can be separated into inspiratory-activated AVPNs (IA-AVPNs) and inspiratory-inhibited AVPNs (II-AVPNs). IA-AVPNs are activated by excitatory presynaptic inputs during inspiratory bursts, but the composition and the roles of these excitatory inputs still remain obscure. II-AVPNs are inhibited by inhibitory presynaptic inputs but whether these inhibitory inputs are regulated by excitatory inputs is also unclear. In the current study, AVPNs were retrogradely fluorescent labeled. The IA-AVPNs were discriminated from II-AVPNs by their different synaptic inputs during inspiratory bursts. The excitatory inputs to IA-AVPNs and the presynaptic regulation of II-AVPNs were examined by whole-cell patch clamping. Topical application of 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX) to the recorded IA-AVPNs almost abolished the tonic EPSCs during inspiratory intervals, inhibited the phasic excitatory currents during inspiratory bursts and attenuated the phasic inspiratory inward currents (PIICs) driven by central inspiratory activity. Blockade of α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) respectively inhibited PIICs in some IA-AVPNs. Carbenoxolone, a gap junction uncoupler, partly inhibited the PIICs of IA-AVPNs. Focal application of CNQX to the II-AVPNs significantly inhibited the frequency, peak amplitude and area of the phasic inspiratory outward currents (PIOCs). These findings demonstrated that glutamatergic non-NMDA receptors played a predominant role in the excitatory drive to the IA-AVPNs, and that α4β2, α7 nAChRs and gap junctions were also rhythmically activated by central inspiratory activity. Additionally, glycinergic neurons making inhibitory inputs to the II-AVPNs were pre-synaptically facilitated by excitatory glutamatergic synaptic inputs.

The 1980s: d-AP5, LTP and a Decade of NMDA Receptor Discoveries

In the 1960s and 70s, biochemical and pharmacological evidence was pointing toward glutamate as a synaptic transmitter at a number of distinct receptor classes, known as NMDA and non-NMDA receptors. The field, however, lacked a potent and highly selective antagonist to block these putative postsynaptic receptors. So, the discoveries in the early 1980s of d-AP5 as a selective NMDA receptor antagonist and of its ability to block synaptic events and plasticity were a major breakthrough leading to an explosion of knowledge about this receptor subtype. During the next 10 years, the role of NMDA receptors was established in synaptic transmission, long-term potentiation, learning and memory, epilepsy, pain, among others. Hints at pharmacological heterogeneity among NMDA receptors were followed by the cloning of separate subunits. The purpose of this review is to recognize the important contributions made in the 1980s by Graham L. Collingridge and other key scientists to the advances in our understanding of the functions of NMDA receptors throughout the central nervous system.