Role of excitatory amino acid receptors in synaptic transmission in area CA1 of rat hippocampus

The new antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), which blocks responses to kainate and quisqualate, has been used in conjunction with D-2-amino-5-phosphonovalerate (APV), which blocks selectively responses to N-methyl-D-aspartate (NMDA), to determine the role of excitatory amino acid receptors in synaptic transmission. An excitatory postsynaptic potential (EPSP)-inhibitory postsynaptic potential (IPSP) sequence was evoked in CA1 neurons by stimulation of the Schaffer collateral-commissural pathway in rat hippocampal slices. CNQX (10 microM) substantially reduced the EPSP without having any effect on input resistance or membrane potential. The IPSP was also reduced provided that the stimulating electrode was place approximately 1 mm from the recording electrode. The EPSP that remained in the presence of CNQX had characteristics of an NMDA receptor-mediated potential; it had a slow timecourse, summated at high frequencies, was blocked reversibly by APV, increased greatly in size in Mg2+-free medium, and showed an anomalous voltage dependence in Mg2+-containing medium. In the presence of CNQX, an APV-sensitive polysynaptic GABAergic IPSP could be evoked, indicating that NMDA receptors can mediate suprathreshold EPSPS in inhibitory interneurons. It is suggested that either NMDA or non-NMDA receptors can, under different circumstances, mediate the synaptic excitation of pyramidal neurons and inhibitory interneurons in area CA1 of the hippocampus.     

Analysis of function of the glutamatergic and GABAergic mediator systems in the olfactory cortex of spontaneously hipertensive rats in vitro

The effect of persistent hypertension on neuronal activity and synaptic transmission has been studied on olfactory cortex slices of SHR rats. The profilies of focal potentials in hypertensive rats demonstrated a short duration of the 2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)-propanoic acid (AMPA) component of excitatory postsynaptic potential (EPSP), a small amplitude and long duration of the N-methyl D-aspartate (NMDA) component of EPSP, and a large amplitude of the GABA_B-dependent slow inhibitory postsynaptic potentials. The sensitivity of glutamate receptors responsible for the generation of AMPA- and NMDA-mediated EPSPs was low after the exposure to 1 mM L-glutamate. The amplitudes of the AMPA- and NMDA-mediated EPSPs decreased. Tetanization of slices from hypertensive rats induced a short-term potentiation followed by a depression. The data obtained indicate that persistent hypertension has depressive effects on the basic glutamatergic and GABAergic parameters of synaptic activity of neurons as well as on learning and memory. Apparently, these processes were evoked by glutamate excitotoxicity in the brain of hypertensive rats.     

A persistent postsynaptic modification mediates long-term potentiation in the hippocampus

Long-term potentiation (LTP) is a long-lasting enhancement of synaptic transmission that can be induced by brief repetitive stimulation of excitatory pathways in the hippocampus. One of the most controversial points is whether the process underlying the enhanced synaptic transmission occurs pre- or postsynaptically. To examine this question, we have taken advantage of the novel physiological properties of excitatory synaptic transmission in the CA1 region of the hippocampus. Synaptically released glutamate activates both NMDA and non-NMDA receptors on pyramidal cells, resulting in an excitatory postsynaptic potential (EPSP) with two distinct components. A selective increase in the non-NMDA component of the EPSP was observed with LTP. This result suggests that the enhancement of synaptic transmission during LTP is caused by an increased sensitivity of the postsynaptic neuron to synaptically released glutamate.     

Both NMDA and non-NMDA subtypes of glutamate receptors are concentrated at synapses on cerebral cortical neurons in culture.

N-methyl-D-aspartate (NMDA) and non-NMDA receptors play a key role in synaptic transmission and plasticity in the vertebrate central nervous system. Previous studies have suggested that although both receptor types are present at synapses, the NMDA receptors may be relatively uniformly distributed. We have combined iontophoretic mapping of NMDA and non-NMDA receptors with immunohistochemical localization of synaptic vesicles along dendrites of single neocortical neurons to determine the relationship between NMDA and non-NMDA receptor distribution and the location of synapses. We find that when corrections for glutamate diffusion are made, NMDA responses are concentrated at focal "hot spots" that coincide with non-NMDA hot spots and that there is an excellent correlation between these hot spots and synapses.     

Glutamate evokes firing through activation of kainate receptors in chick accessory lobe neurons

Ten pairs of protrusions, called accessory lobes (ALs), exist at the lateral sides of avian lumbosacral spinal cords. Histological and behavioral evidence suggests that neurons are present in ALs and the AL acts as a sensory organ of equilibrium during walking. Neurons in the outer layer of the AL consistently show glutamate-like immunoreactivity and neurons in the central region of the AL show glutamate receptor-like immunoreactivity. However, it is unknown how glutamate acts on the functional activity of AL neurons. In this study, we examined the effects of glutamate on the electrical activities of AL neurons using the patch clamp technique. There are two types of neurons among isolated AL neurons: spontaneously firing and silent neurons. Among silent neurons, 42 % of neurons responded to glutamate and generated repetitive firing. Kainate and glutamate in combination with the NMDA receptor antagonist, MK-801, also induced firing and evoked an inward current. On the other hand, the application of AMPA, NMDA or glutamate in combination with the non-NMDA receptor antagonist, CNQX, did not. These results indicate that chick AL neurons express functional kainate receptors to respond to glutamate and suggest that the glutamatergic transmission plays a role in excitatory regulation of AL neurons of the chick.     

Long-term potentiation in the neurons of the edible snail

A brief high-frequency stimulation of the anal nerve of the isolated nerve ring of snail Helix induced a pronounced increase in the amplitude of EPSPs, evoked in identified neurons of left parietal and visceral ganglions by low frequency (once in 5 min) stimulation of the same nerve. The amplitude of EPSP returned to the control level 30-120 min after tetanization. We called this effect long-term potentiation. A brief application of serotonin (10 microM) in the majority of neurons also induced lasting either 15-30 min or more than 2 hours facilitation of EPSP, evoked by anal nerve stimulation. Intracellular cAMP injections, being without effect on EPSP amplitude in many neurons, in certain neurons caused an increase in EPSP amplitude, lasting up to 30 min. It is suggested that the 3 factors shown to increase synaptic efficiency in molluscan neurons may have common mechanisms of action.     

Electrical advantages of dendritic spines

Many neurons receive excitatory glutamatergic input almost exclusively onto dendritic spines. In the absence of spines, the amplitudes and kinetics of excitatory postsynaptic potentials (EPSPs) at the site of synaptic input are highly variable and depend on dendritic location. We hypothesized that dendritic spines standardize the local geometry at the site of synaptic input, thereby reducing location-dependent variability of local EPSP properties. We tested this hypothesis using computational models of simplified and morphologically realistic spiny neurons that allow direct comparison of EPSPs generated on spine heads with EPSPs generated on dendritic shafts at the same dendritic locations. In all morphologies tested, spines greatly reduced location-dependent variability of local EPSP amplitude and kinetics, while having minimal impact on EPSPs measured at the soma. Spine-dependent standardization of local EPSP properties persisted across a range of physiologically relevant spine neck resistances, and in models with variable neck resistances. By reducing the variability of local EPSPs, spines standardized synaptic activation of NMDA receptors and voltage-gated calcium channels. Furthermore, spines enhanced activation of NMDA receptors and facilitated the generation of NMDA spikes and axonal action potentials in response to synaptic input. Finally, we show that dynamic regulation of spine neck geometry can preserve local EPSP properties following plasticity-driven changes in synaptic strength, but is inefficient in modifying the amplitude of EPSPs in other cellular compartments. These observations suggest that one function of dendritic spines is to standardize local EPSP properties throughout the dendritic tree, thereby allowing neurons to use similar voltage-sensitive postsynaptic mechanisms at all dendritic locations.     

Effects of etomidate on descending activation of motoneurons in neonatal rat spinal cord in vitro

Descending activation pathways in spinal cord are essential for inducing and modulating autokinesis, but whether the effects of general anesthetic agents on the descending pathways are involved in initiation of skeletal muscle relaxation or not, as well as the underlying mechanisms on excitatory amino acid receptors still remain unclear. In order to explore the mechanisms underlying etomidate's effects on descending activation of spinal cord motoneurons (MNs), the conventional intracellular recording techniques in MNs of spinal cord slices isolated from neonatal rats (7-14 days old) were performed to observe and analyze the actions of etomidate on excitatory postsynaptic potential (EPSP) elicited by electrical stimulation of the ipsilateral ventrolateral funiculus (VLF), which was named VLF-EPSP. Etomidate at 0.3, 3.0 (correspond to clinical concentration) and 30.0 μmol/L were in turn perfused to MN with steadily recorded VLF-EPSPs. At low concentration (0.3 μmol/L), etomidate increased duration, area under curve and/or half-width of VLF-EPSP and N-methyl-D-aspartate (NMDA) receptor-mediated VLF-EPSP component (all P < 0.05), as well as amplitude, area under curve and half-width of non-NMDA receptor-mediated VLF-EPSP component (all P < 0.05), or decreased amplitude and area under curve of VLF-EPSP, its NMDA receptor component, and non-NMDA receptor component (all P < 0.05). However, at 3.0 and 30.0 μmol/L, it was only observed that etomidate exerted inhibitory effects on amplitude and/or duration and/or area under curve of VLF-EPSP (P < 0.05 or P < 0.01) with concentration- and time-dependent properties. Moreover, NMDA receptor-mediated VLF-EPSP component was more sensitive to etomidate at ≥ 3.0 μmol/L than non-NMDA receptor-mediated VLF-EPSP component did. As a conclusion, etomidate, at different concentrations, exerts differential effects on VLF-EPSP and glutamate receptors mediating the synaptic transmission of descending activation of MNs in neonatal rat spinal cord in vitro.     

Cell-type specificity of mGluR activation in striatal neuronal subtypes

Summary. The effects of metabotropic glutamate receptor (mGluR) activation were studied in medium spiny neurons and large aspiny (LA) interneurons by means of electrophysiological and optical recordings. DCG-IV and L-SOP, agonists for group II and III mGluRs, respectively, produced a presynaptic inhibitory effect on corticostriatal glutamatergic excitatory postsynaptic potentials (EPSPs) in both spiny and LA cells. Activation of group I mGluRs by the selective agonist 3,5-DHPG produced no effect on membrane properties and glutamatergic transmission in spiny neurons, whereas it did cause a membrane depolarization in LA interneurons coupled to increased input resistance. In combined optical and electrophysiological experiments, in spiny neurons 3,5-DHPG enhanced membrane depolarization and intracellular calcium (Ca²⁺) levels induced by NMDA applications, but not in LA interneurons. These data suggest the existence of a positive interaction between NMDA and group I mGlu receptors only in medium spiny cells which might, at least partially, account for the differential vulnerability to excitotoxic damage observed in striatal neuronal subtypes. Accepted September 20, 1999     

P2Y(1) receptor activation inhibits NMDA receptor-channels in layer V pyramidal neurons of the rat prefrontal and parietal cortex

In the 1st part of this study, monosynaptic excitatory postsynaptic potentials (EPSPs) in layer V of the rat prefrontal cortex (PFC) were evoked by electrical stimulation of layer I. Recordings with intracellular sharp, microelectrodes showed a concentration-dependent inhibition of the EPSP by adenosine 5'-O-(2-thiodiphosphate) (ADP-beta-S). Pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), when given alone depressed the EPSP and in addition antagonized the effect of ADP-beta-S. Exclusion of the N-methyl-D-aspartate (NMDA) component of the EPSP by D(.)-amino-5-phosphonopentanoic acid (AP-5) abolished the ADP-beta-S-induced depression. The pressure-application of both NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) caused reproducible depolarizations. ADP-beta-S inhibited the effect of NMDA, but did not alter that of AMPA. PPADS was also under these conditions antagonistic with ADP-beta-S. In the 2nd part of the study, NMDA-induced currents were measured by whole-cell patch-clamp pipettes. ADP-beta-S caused a concentration-dependent inhibition of the responses to NMDA. PPADS alone did not alter the NMDA-currents but again antagonized the action of ADP-beta-S; 2'-deoxy-N(6)-methyladenosine-3',5'-diphosphate (MRS 2179) also abolished the NMDA effect. The ADP-beta-S-induced inhibition persisted in the presence of tetrodotoxin (TTX) or guanosine 5'-O-(3-thiodiphosphate) (GDP-beta-S) applied to the external medium and the pipette solution, respectively. The 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) moderately decreased the ADP-beta-S effect. The inhibitory function of ADP-beta-S on EPSPs and the interaction with PPADS was observed also in layer V pyramidal neurons of the parietal somatosensory cortex. In conclusion, metabotropic P2Y(1) receptors appear to exert a new modulatory influence on fast excitatory amino acid transmission in the cerebral cortex.     

Effects of low-frequency tetanic stimulation of the synaptic inputs on different forms of long-term potentiation in the rat hippocampus

In experiments on transversal slices of the dorsal hippocampus of rats, we found that low-frequency stimulation of the mossy fibers (MF) against the background of pre-settled long-term post-tetanic potentiation in the MF-CA3 pyramidal neuron (PN) dendrites synaptic system evoked depotentiation in all studied slices. Depotentiation was considerably decreased by a non-competitive blocker of the NMDA glutamate receptors, ketamine (100 μM), as well as by an inhibitor of calmodulin, trifluoroperazine (10 μM), and an inhibitor of calcineurin, cyclosporin A (250 μM). At the same time, depontentiation was not changed by 50 μM polymixin B, an inhibitor of protein kinase C. Long-term potentiation of synaptic transmission in the Schaffer collaterals (SchC)-CA1 PN dendrites system, which was evoked by 2.5-min-long anoxia/aglycemia episodes, resulted exclusively from enhancement of the NMDA component of population EPSP, while their AMPA component was not modified, i.e., in this case potentiation was of a postsynaptic nature. Under these conditions, low-frequency stimulation of SchC resulted in a further increase in the intensity of synaptic transmission due to increases in both the NMDA and AMPA components of population EPSP. The above form of potentiation could be suppressed by 100 μM ketamine, 10 μM trifuoroperazine, 250 μM cyclosporin A, or 10 μM N-nitro-L-arginine. Weak (near-threshold) high-frequency stimulation of SchC induced long-lasting potentiation of synaptic transmission due to an isolated increase in the AMPA component of population EPSP, i.e., this potentiation was of a postsynaptic nature. In the latter case, low-frequency SchC stimulation resulted in further facilitation of synaptic transmission. Intensive tetanic high-frequency stimulation of the above fibers induced long-term potentiation of a presynaptic nature, while their low-frequency stimulation depotentiated synaptic transmission.     

Mechanisms generating the time course of dual component excitatory synaptic currents recorded in hippocampal slices

We studied with the whole-cell recording techniques, the mechanisms underlying the time course of the slow N-methyl-D-aspartate (NMDA), and fast non-NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) in hippocampal slices. The rising phase of the NMDA receptor-mediated component of the EPSC as well as the decaying phase of the NMDA and non-NMDA component were highly temperature-sensitive, suggesting that neither of these processes is determined by free diffusion of transmitter. Moreover, glutamate uptake blockers enhanced the responses to exogenously applied glutamate, but had no effect on the decay of either the NMDA or non-NMDA components of the EPSCs. On the other hand, open channel blockers known to modify NMDA channel kinetics reduced the EPSC decay time. Thus, the present results support a model in which the rise time and decay of the NMDA component are determined primarily by slow channel kinetics and the decay of the non-NMDA component is due either to channel kinetics or to desensitization.     

Endogenous Interleukin-1β in Neuropathic Rats Enhances Glutamate Release from the Primary Afferents in the Spinal Dorsal Horn through Coupling with Presynaptic N-Methyl-d-aspartic Acid Receptors

Excessive activation of glutamate receptors and overproduction of proinflammatory cytokines, including interleukin-1β (IL-1β) in the spinal dorsal horn, are key mechanisms underlying the development and maintenance of neuropathic pain. In this study, we investigated the mechanisms by which endogenous IL-1β alters glutamatergic synaptic transmission in the spinal dorsal horn in rats with neuropathic pain induced by ligation of the L5 spinal nerve. We demonstrated that endogenous IL-1β in neuropathic rats enhances glutamate release from the primary afferent terminals and non-NMDA glutamate receptor activities in postsynaptic neurons in the spinal dorsal horn. Myeloid differentiation primary response protein 88 (MyD88) is a mediator used by IL-1β to enhance non-NMDA glutamate receptor activities in postsynaptic neurons in the spinal dorsal horn. Presynaptic NMDA receptors are effector receptors used by the endogenous IL-1β to enhance glutamate release from the primary afferents in neuropathic rats. This is further supported by the fact that NMDA currents recorded from small neurons in the dorsal root ganglion of normal rats are potentiated by exogenous IL-1β. Furthermore, we provided evidence that functional coupling between IL-1β receptors and presynaptic NMDA receptors at the primary afferent terminals is mediated by the neutral sphingomyelinase/ceramide signaling pathway. Hence, functional coupling between IL-1β receptors and presynaptic NMDA receptors at the primary afferent terminals is a crucial mechanism leading to enhanced glutamate release and activation of non-NMDA receptors in the spinal dorsal horn neurons in neuropathic pain conditions. Interruption of such functional coupling could be an effective approach for the treatment of neuropathic pain.     

Contribution of NMDA and non-NMDA glutamate receptors to locomotor pattern generation in the neonatal rat spinal cord.

The motor programme executed by the spinal cord to generate locomotion involves glutamate-mediated excitatory synaptic transmission. Using the neonatal rat spinal cord as an in vitro model in which the locomotor pattern was evoked by 5-hydroxytryptamine (5-HT), we investigated the role of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in the generation of locomotor patterns recorded electrophysiologically from pairs of ventral roots. In a control solution, 5-HT (2.5-30 microM) elicited persistent alternating activity in left and right lumbar ventral roots. Increasing 5-HT concentration within this range resulted in increased cycle frequency (on average from 8 to 20 cycles min-1). In the presence of NMDA receptor antagonism, persistent alternating activity was still observed as long as 5-HT doses were increased (range 20-40 microM), even if locomotor pattern frequency was lower than in the control solution. In the presence of non-NMDA receptor antagonism, stable locomotor activity (with lower cycle frequency) was also elicited by 5-HT, albeit with doses larger than in the control solution (15-40 microM). When NMDA and non-NMDA receptors were simultaneously blocked, 5-HT (5-120 microM) always failed to elicit locomotor activity. These data show that the operation of one glutamate receptor class was sufficient to express locomotor activity. As locomotor activity developed at a lower frequency than in the control solution after pharmacological block of either NMDA or non-NMDA receptors, it is suggested that both receptor classes were involved in locomotor pattern generation.     

Excitatory Amino Acid Receptors Coupled to the Nitric Oxide/Cyclic GMP Pathway in Rat Cerebellum During Development

The coupling of excitatory amino acid receptors to the formation of nitric oxide (NO) from arginine during the postnatal development of rat cerebellum was assayed in slice preparations by measuring cyclic GMP accumulation. In the immature tissue, N-methyl-D-aspartate (NMDA) and glutamate were highly efficacious agonists, whereas alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and quisqualate evoked only small responses. The effect of glutamate at all concentrations tested (up to 10 mM) was abolished by the NMDA antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801). In adult slices, AMPA and quisqualate were much more effective and their effects were inhibited by 6-cyano-7-nitroquinoxaline-2,3-dione, an antagonist for ionotropic non-NMDA receptors, whereas the apparent efficacy of NMDA was greatly reduced. The major changes took place between 8 and 14 days postnatum and, in the case of NMDA, part of the loss of sensitivity appeared to reflect a decline in the ambient levels of glycine with age. Moreover, a component of the response to glutamate in the adult was resistant to MK-801. Cyclic GMP accumulations induced by NMDA and non-NMDA agonists alike were Ca(2+)-dependent and could be antagonized by competitive NO synthase inhibitors in an arginine-sensitive manner, indicating that they are all mediated by NO formation. With one of the inhibitors, L-NG-nitroarginine, a highly potent component (IC50 = 6 nM) evident in slices from rats of up to 8 days old was lost during maturation, indicating that there may be a NO synthase isoform which is prominent only in the immature tissue. Cyclic GMP levels in adult slices under "basal" conditions were reduced markedly by blocking NMDA receptors, by inhibiting action potentials with tetrodotoxin, or by NO synthase inhibition, suggesting that the endogenous transmitter released during spontaneous synaptic activity acts mainly through NMDA receptors to trigger NO formation.     

Excitatory amino acid receptor-channels in Purkinje cells in thin cerebellar slices.

Glutamate receptors of the N-methyl-D-aspartate (NMDA) and non-NMDA type serve different functions during excitatory synaptic transmission. Although many central neurons bear both types of receptor, the evidence concerning the sensitivity of cerebellar Purkinje cells to NMDA is contradictory. To investigate the receptor types present in Purkinje cells, we have used whole-cell and outside-out patch-clamp methods to record from cells in thin cerebellar slices from young rats. At a holding potential of -70 mV (in nominally Mg(2+)-free medium, with added glycine) NMDA caused a whole-cell current response which consisted of a dramatic increase in the frequency of synaptic currents. In the presence of tetrodotoxin (TTX) and the gamma-aminobutyric acidA (GABAA) receptor antagonist bicuculline, spontaneous synaptic currents and responses to NMDA were inhibited. In a proportion of cells a small polysynaptic response to NMDA persisted, which was further reduced by the non-NMDA receptor antagonist 6-cyano-2,3-dihydro-7-nitroquinoxalinedione (CNQX). The non-NMDA glutamate receptor agonists kainate (KA), quisqualate (QA) and s-alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (s-AMPA), evoked large inward currents due to the direct activation of receptors in Purkinje cells. NMDA applied to excised membrane patches failed to evoke any single-channel currents, whereas s-AMPA and QA caused small inward currents accompanied by marked increases in current noise. Spectral analysis of the s-AMPA noise in patches gave an estimated mean channel conductance of approximately 4 pS.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of excitatory amino acids in synaptic transmission in the hippocampus

We have highlighted some aspects of the action of excitatory amino acid transmission in the hippocampus. Fast epsps can be blocked by CNQX to reveal a component of synaptic transmission which is mediated by NMDA receptors. Extracellular recordings of ionic activities show that NMDA and non-NMDA ionophores are permeable to the major monovalent cations, while NMDA ionophores also appear to be permeable to Ca2+. Interactions of agonists applied by iontophoresis may be correlates of phenomena such as LTP, which can be evoked by appropriate synaptic stimulation.     

Simulation and Parameter Estimation Study of a Simple Neuronal Model of Rhythm Generation: Role of NMDA and Non-NMDA Receptors

Simple neural network models of the Xenopus embryo swimming CPG, based on the one originally developed by Roberts and Tunstall (1990), were used to investigate the role of the voltage-dependent N-methyl-D-aspartate (NMDA) receptor channels, in conjunction with faster non-NMDA components of synaptic excitation, in rhythm generation. The voltage-dependent NMDA current "follows" the membrane potential, leading to a postinhibitory rebound that is more efficient than one without voltage dependency and allows neurons to fire more than one action potential per cycle. Furthermore, the model demonstrated limited rhythmic activity in the absence of synaptic inhibition, supporting the hypothesis that the NMDA channels provide a basic mechanism for rhythmicity. However, the rhythmic properties induced by the NMDA current were observed only when there was moderate activation of the non-NMDA synaptic channels, suggesting a modulatory role for this component. The simulations also show that the voltage dependency of the NMDA conductance, as well as the fast non-NMDA current, stabilizes the alternation pattern versus synchrony. To verify that these effects and their implications on the mechanism of swimming and transition to other types of activity take place in the real preparation, constraints on parameter values have to be specified. A method to estimate synaptic parameters was tested with generated data. It is shown that a global analysis, based on multiple iterations of the optimization process (Foster et al., 1993), gives a better understanding of the parameter subspace describing network activity than a standard fit with a sensitivity analysis for an individual solution.     

Blockade of desensitization augments quisqualate excitotoxicity in hippocampal neurons

Glutamate neurotoxicity is thought to play a role in the pathogenesis of several neurodegenerative diseases. While prolonged activation of either NMDA or non-NMDA receptors causes neuronal damage, NMDA receptors appear to mediate most of the glutamate toxicity. The reasons why NMDA toxicity predominates are uncertain but may relate to more effective neuroprotective mechanisms acting at non-NMDA receptors. To determine whether desensitization is one such mechanism, we studied the effects of the lectin wheat germ agglutinin (WGA) on quisqualate currents and toxicity in cultured postnatal rat hippocampal neurons. After WGA treatment, quisqualate currents exhibit little desensitization and a 4- to 8-fold increase in steady-state amplitude. WGA also markedly augments the degree of acute, quisqualate-induced neuronal degeneration. These results suggest that non-NMDA desensitization serves a neuroprotective function in hippocampal neurons.     

The heterogeneity of the excitatory synaptic inputs in the spinal motor neurons of the frog Rana ridibunda

The synaptic responses induced in motoneurones by the stimulations of the dorsal root (DR), single afferent fibres and reticular formation (RF) were intracellularly recorded in the isolated frog spinal cord. It was shown that argiopine (the selective blocker of glutamate receptors of non-NMDA type) in concentrations ranging from 3.10(-7) to 1.10(-5) M effectively suppressed the di- and polysynaptic, but not the monosynaptic components of EPSP's induced by DR stimulation. The initial reaction to argiopine consisted of the increase of this monosynaptic component of EPSP. In the same concentrations range, argiopine reduced both mono- and polysynaptic EPSP, evoked by RF stimulation. 2-amino-phosphonovaleric acid (1.10(-4) M) did not affect, whereas the kinurenate (1--2.10(-3) M) completely blocked the amplitude of all kinds of synaptic responses. The various effects of argiopine on the responses induced by microstimulation of presynaptic nerve terminals were observed. The data obtained speak in favour of heterogeneity of monosynaptic excitatory inputs in the motoneurones of frog spinal cord. Being the glutamatergic by nature, the inputs differ in the properties of postsynaptic receptors. All of these receptors concerning to non NMDA-type can be divided to argiopine-sensitive and argiopine-resistant. The first seem to be involved in the monosynaptic connections of RF and the second--in those of primary afferents with motoneurones.