Component Of Excitatory Postsynaptic Potentials Research Articles

Subtype-specific effects of dopaminergic D2 receptor activation on synaptic trains in layer V pyramidal neurons in the mouse prefrontal cortex.

In humans, prefrontal cortical areas are known to support executive functions. In mice, these functions are mediated by homologous regions in the medial prefrontal cortex (mPFC). Executive processes are critically dependent on optimal levels of dopamine (DA), but the cellular mechanisms of DA modulation are incompletely understood. Stable patterns of neuronal activity may be sensitive to frequency‐dependent changes in synaptic transmission. We characterized the effects of D2 receptor (D2R) activation on short‐term excitatory postsynaptic potential (EPSP) dynamics evoked at varying frequencies in the two subtypes of layer V pyramidal neurons in mouse mPFC. We isolated NMDA receptor and non‐NMDA receptor‐mediated components of EPSP trains evoked by stimulating fibers within layer V or layer I. All significant effects of D2 receptor activation were confined to type I (corticopontine) cells. First, we found that with layer I stimulation, D2R activation reduces the amplitude of NMDAR‐mediated EPSPs, with no effect on facilitation or depression of these responses at lower frequencies, but leading to facilitation with high frequency stimulation. Further, the non‐NMDA component also underwent synaptic depression at low frequencies. Second, with layer V stimulation, D2R activation had no effect on NMDA or non‐NMDA receptor‐mediated EPSP components. Overall, our results suggest that D2R activation may modulate memory functions by inhibiting ‘top‐down’ influences from apical tuft inputs activated at low frequencies, while promoting ‘top‐down’ influences from inputs activated at higher frequencies. These data provide further insight into mechanisms of dopamine's modulation of executive functions.

Multiple Subtypes of Serotonin Receptors in the Feeding Circuit of a Pond Snail

In the central nervous system of the pond snail Lymnaea stagnalis, serotonergic transmission plays an important role in controlling feeding behavior. Recent electrophysiological studies have claimed that only metabotropic serotonin (5-HT(2)) receptors, and not ionotropic (5-HT(3)) receptors, are used in synapses between serotonergic neurons (the cerebral giant cells, CGCs) and the follower buccal motoneurons (the B1 cells). However, these data are inconsistent with previous results. In the present study, we therefore reexamined the serotonin receptors to identify the receptor subtypes functioning in the synapses between the CGCs and the B1 cells by recording the compound excitatory postsynaptic potential (EPSP) of the B1 cells evoked by a train of stimulation to the CGC in the presence of antagonists: cinanserin for 5-HT(2) and/or MDL72222 for 5-HT(3). The compound EPSP amplitude was partially suppressed by the application of these antagonists. The rise time of the compound EPSP was longer in the presence of MDL72222 than in that of cinanserin. These results suggest that these two subtypes of serotonin receptors are involved in the CGC-B1 synapses, and that these receptors contribute to compound EPSP. That is, the fast component of compound EPSP is mediated by 5-HT(3)-like receptors, and the slow component is generated via 5-HT(2)-like receptors.

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 GABAB-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.

Axonal Speeding: Shaping Synaptic Potentials in Small Neurons by the Axonal Membrane Compartment

The role of the axonal membrane compartment in synaptic integration is usually neglected. We show here that in interneurons of the cerebellar molecular layer, where dendrites are so short that the somatodendritic domain can be considered isopotential, the axonal membrane contributes a significant part of the cell input capacitance. We examine the impact of axonal membrane on synaptic integration by cutting the axon with two-photon illumination. We find that the axonal compartment acts as a sink for signals generated at fast conductance synapses, thus increasing the initial decay rate of corresponding synaptic potentials over the value predicted from the resistance-capacitance (RC) product of the cell membrane; signals generated at slower synapses are much less affected. This mechanism sharpens the spike firing precision of fast glutamatergic inputs without resorting to multisynaptic pathways.

Selective Shunting of the NMDA EPSP Component by the Slow Afterhyperpolarization in Rat CA1 Pyramidal Neurons

Pyramidal neuron dendrites express voltage-gated conductances that control synaptic integration and plasticity, but the contribution of the Ca(2+)-activated K(+)-mediated currents to dendritic function is not well understood. Using dendritic and somatic recordings in rat hippocampal CA1 pyramidal neurons in vitro, we analyzed the changes induced by the slow Ca(2+)-activated K(+)-mediated afterhyperpolarization (sAHP) generated by bursts of action potentials on excitatory postsynaptic potentials (EPSPs) evoked at the apical dendrites by perforant path-Schaffer collateral stimulation. Both the amplitude and decay time constants of EPSPs (tau(EPSP)) were reduced by the sAHP in somatic recordings. In contrast, the dendritic EPSP amplitude remained unchanged, whereas tau(EPSP) was reduced. Temporal summation was reduced and spatial summation linearized by the sAHP. The amplitude of the isolated N-methyl-D-aspartate component of EPSPs (EPSP(NMDA)) was reduced, whereas tau(NMDA) was unaffected by the sAHP. In contrast, the sAHP did not modify the amplitude of the isolated EPSP(AMPA) but reduced tau(AMPA) both in dendritic and somatic recordings. These changes are attributable to a conductance increase that acted mainly via a selective "shunt" of EPSP(NMDA) because they were absent under voltage clamp, not present with imposed hyperpolarization simulating the sAHP, missing when the sAHP was inhibited with isoproterenol, and reduced under block of EPSP(NMDA). EPSPs generated at the basal dendrites were similarly modified by the sAHP, suggesting both a somatic and apical dendritic location of the sAHP channels. Therefore the sAHP may play a decisive role in the dendrites by regulating synaptic efficacy and temporal and spatial summation.

Developmental differences in neuromodulation and synaptic properties in the lamprey spinal cord

Functional properties in the spinal cord change during development to adapt motor outputs to differing behavioral requirements. Here, we have examined whether there are also developmental differences in spinal cord plasticity by comparing the neuromodulatory effects of substance P in the larval lamprey spinal cord with its previously characterized effects in premigratory adults.The premigratory adult effects of substance P were all significantly reduced in larvae. As the adult effects of substance P depend on the N-methyl-d-aspartate (NMDA)-dependent potentiation of glutamatergic synaptic transmission, we examined if the developmental differences in neuromodulation were associated with differences in synaptic properties. We found that the amplitude, rise time, and half-width of excitatory postsynaptic potentials (EPSPs) from excitatory network interneurons were all significantly reduced in larvae compared with adults. These differences were associated with a reduction in the NMDA component of larval EPSPs, an effect that could have contributed to the reduced modulatory effects of substance P in larvae. In contrast to glutamatergic inputs, the amplitude, rise time, and half-width of inhibitory postsynaptic potentials (IPSPs) from ipsilateral inhibitory interneurons were all significantly increased in larvae compared with adults. Substance P also potentiated larval IPSP amplitudes, an effect not seen in adults. This increase in inhibition contributed to the reduced effects of substance P in larvae, as premigratory adult-like modulation could be evoked when inhibition was blocked with strychnine.These results suggest that opposite developmental changes in excitatory and inhibitory synaptic transmission and their modulation are associated with developmental differences in spinal cord neuromodulation.

Synaptic facilitation and enhanced neuronal excitability in the submucosal plexus during experimental colitis in guinea‐pig

Intestinal secretion is regulated by submucosal neurones of the enteric nervous system. Inflammation of the intestines leads to aberrant secretory activity; therefore we hypothesized that the synaptic and electrical behaviours of submucosal neurones are altered during colitis. To test this hypothesis, we used intracellular microelectrode recording to compare the excitability and synaptic properties of submucosal neurones from normal and trinitrobenzene sulphonic acid (TNBS)-inflamed guinea-pig colons. Inflammation differentially affected the electrophysiological characteristics of the two functional classes of submucosal neurones. AH neurones from inflamed colons were more excitable, had shorter action potential durations and reduced afterhyperpolarizations. Stimulus-evoked fast and slow excitatory postsynaptic potentials (EPSPs) in S neurones were larger during colitis, and the incidence of spontaneous fast EPSPs was increased. In control preparations, fast EPSPs were almost completely blocked by the nicotinic receptor antagonist hexamethonium, whereas fast EPSPs in inflamed S neurones were only partially inhibited by hexamethonium. In inflamed tissues, components of the fast EPSP in S neurones were sensitive to blockade of P2(X) and 5-HT(3) receptors while these antagonists had little effect in control preparations. Control and inflamed S neurones were equally sensitive to brief application of acetylcholine, ATP and 5-HT, suggesting that synaptic facilitation was due to a presynaptic mechanism. Immunoreactivity for 5-HT in the submucosal plexus was unchanged by inflammation; this indicates that altered synaptic transmission was not due to anatomical remodelling of submucosal nerve terminals. This is the first demonstration of alterations in synaptic pharmacology in the enteric nervous system during inflammation.

Ketamine blocks non-N-methyl-D-aspartate receptor channels attenuating glutamatergic transmission in the auditory cortex

ObjectiveTo investigate the influence of ketamine on non-N-methyl-D-aspartate (NMDA) receptor-mediated synaptic transmission in the auditory cortex. Material and MethodsUsing whole-cell patch-clamp techniques on pyramidal neurons, we studied the effects of ketamine on excitatory post-synaptic potentials (EPSPs) evoked by electrical stimulation of internal capsule fibers in slices of gerbil auditory cortex. ResultsAfter blockade of the slow, NMDA receptor-mediated EPSP component with dl-2-amino-5-phosphonovaleric acid, application of ketamine in a concentration-dependent manner led to a reduction in the amplitude of fast, 6-cyano-7-nitroquinoxalinedione (CNQX)-sensitive EPSPs, accompanied by an increased membrane resistance. Blockade of non-NMDA glutamate receptors with CNQX prevented both effects. ConclusionKetamine reduces membrane conductance and glutamatergic excitation, in part by blocking alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor channels that may be constitutively active at a low level in slice preparations of auditory cortex.

Estradiol increases delayed, N-methyl- d-aspartate receptor-mediated excitation in the hippocampal CA1 region

Hippocampal functions, e.g. synaptic plasticity and hippocampal-dependent behavior, are influenced by the circulating levels of ovarian steroids in adult, female rats. The mechanisms underlying this estradiol-dependent modulation, however, are poorly understood. One possibility is that estradiol alters N-methyl- d-aspartate (NMDA)-receptor functioning in the hippocampus. Here, using the in vitro hippocampal slice preparation, we evaluate estradiol-dependent changes in the NMDA receptor- and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated components of excitatory postsynaptic potentials (EPSPs) evoked in CA1 by Schaffer collateral test stimulation. Using established experimental conditions [J Neurosci 17 (1997) 1848], we replicate the observation that estradiol pretreatment of ovariectomized rats increases a pharmacologically isolated NMDA receptor-mediated EPSP evoked by Schaffer collateral stimulation. However, using different conditions that optimize study of this evoked response, the estradiol-dependent increase in the monosynaptic NMDA receptor-mediated EPSP is eliminated. Low-intensity test stimulation of the Schaffer collaterals in this optimized medium reveals a novel, late NMDA receptor-mediated EPSP in CA1 from estradiol-pretreated rats. The mechanism(s) underlying this estradiol-dependent increase in a late, NMDA receptor-mediated EPSP is not known, but enhanced CA1–CA1 excitatory circuitry and glutamate spillover could contribute to this response. We conclude that estradiol pretreatment enhances NMDA receptor function in the female hippocampus by increasing not the monosynaptic, but rather a late NMDA receptor-mediated response. Variations in the magnitude of this late response may well contribute to ovarian steroid-dependent modulation of hippocampal synaptic plasticity.

Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons

Dopamine acts mainly through the D1/D5 receptor in the prefrontal cortex (PFC) to modulate neural activity and behaviors associated with working memory. To understand the mechanism of this effect, we examined the modulation of excitatory synaptic inputs onto layer V PFC pyramidal neurons by D1/D5 receptor stimulation. D1/D5 agonists increased the size of N-methyl-d-aspartate (NMDA) component of excitatory postsynaptic currents (EPSCs) through a postsynaptic mechanism. In contrast, D1/D5 agonists caused a slight reduction in the size of the non-NMDA component of EPSCs through a small decrease in release probability. With 20 Hz synaptic trains, we found that the D1/D5 agonists increased depolarization of summating the NMDA component of excitatory postsynaptic potential (EPSP). By increasing the NMDA component of EPSCs, yet slightly reducing release, D1/D5 receptor activation selectively enhanced sustained synaptic inputs and equalized the sizes of EPSPs in a 20-Hz train.

Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons.

Dopamine acts mainly through the D1/D5 receptor in the prefrontal cortex (PFC) to modulate neural activity and behaviors associated with working memory. To understand the mechanism of this effect, we examined the modulation of excitatory synaptic inputs onto layer V PFC pyramidal neurons by D1/D5 receptor stimulation. D1/D5 agonists increased the size of N-methyl-d-aspartate (NMDA) component of excitatory postsynaptic currents (EPSCs) through a postsynaptic mechanism. In contrast, D1/D5 agonists caused a slight reduction in the size of the non-NMDA component of EPSCs through a small decrease in release probability. With 20 Hz synaptic trains, we found that the D1/D5 agonists increased depolarization of summating the NMDA component of excitatory postsynaptic potential (EPSP). By increasing the NMDA component of EPSCs, yet slightly reducing release, D1/D5 receptor activation selectively enhanced sustained synaptic inputs and equalized the sizes of EPSPs in a 20-Hz train.

Convergence pattern of uncrossed excitatory and inhibitory semicircular canal-specific inputs onto second-order vestibular neurons of frogs

Second-order vestibular neurons of frogs receive converging monosynaptic excitatory and disynaptic excitatory and inhibitory inputs following electrical pulse stimulation of an individual semicircular canal nerve on the ipsilateral side. Here we revealed, in the in vitro frog brain, disynaptic inhibitory postsynaptic potentials (IPSPs) by bath application of antagonists specific for glycine or gamma-aminobutyric acid-A (GABA(A)) receptors. Differences in the response parameters between disynaptic IPSPs and excitatory postsynaptic potentials (EPSPs) suggested that disynaptic IPSPs originated from a more homogeneous subpopulation of thicker vestibular nerve afferent fibers than mono- or disynaptic EPSPs. To investigate a possible size-related organization of these canal-specific, parallel pathways, we combined long-lasting anodal currents of variable intensities with strong cathodal test pulses, to block pulse-evoked responses reversibly in a graded manner according to the size-related sensitivity of vestibular nerve afferent fibers. The anodal current intensity required to block a particular response component was about 15 times lower than the strength of the cathodal test pulse that activated this response component. These large threshold differences were exploited for a selective anodal suppression of the responses from thick vestibular nerve afferent fibers. In fact, response components known to originate exclusively from thick-caliber afferent fibers such as the electrically transmitted monosynaptic EPSP component exhibited the lowest thresholds for cathodal test pulses and were the first to disappear in the presence of small anodal polarization steps. Thresholds for the activation/inactivation of responses and current intensities required for response saturation/blockade were used to assess the fiber spectrum that evoked the different response components. Mono- and disynaptic EPSPs appeared to originate from a broad spectrum of thick and thin vestibular nerve afferent fibers. The spectrum of afferent fibers that activated disynaptic IPSPs on the other hand was more homogeneous and consisted of thick and intermediate fibers. Such a canal-specific and fiber type-related organization of converging inputs of second-order vestibular neurons via feedforward projections was shown for the first time by this study in frogs, but might also prevail in mammals. Similar differences in these feedforward pathways have been proposed earlier in a vestibular side-loop model. Our results are consistent with the basic assumptions of this model and relate to the processing and tuning of dynamic vestibular signals.

Memory consolidation in Hermissenda crassicornis.

Experiments with shell-less molluscs (Aplysia and Hermissenda) have revealed a number of processes that underlie by these organisms and also by some vertebrates. Hermissenda, for example, shows significant Pavlovian conditioning capabilities (1). Follow-up investigations on these molluscs dealt with the sensory stimuli needed for short-term (STM) and long-term (LTM) (2). The relationship of the two memories with in vitro changes in excitatory post-synaptic potentials (EPSPs) have also been investigated in the neural networks of these organisms (3). Many studies of the molecular aspects of these two different regimes have led to quite detailed descriptions of the events (4, 5, 6). Both Aplysia and Hermissenda have been tested for their recall of induced behavioral modifications after one, two, or many conditioning events (CEs). In Aplysia, the EPSP component of produced by 1 CE was compared to that produced by 5 CEs (3). In Hermissenda, the comparison was made between 2 CEs and 9 CEs (2). Five to ten minutes after finishing one or two conditioning events, both animals exhibited significant behavioral recall (i.e. STM); but there was no recall after an hour or more (i.e. no LTM). The larger numbers of CEs, however, did induce LTM in both species. Since STM and LTM are clearly responding to a different set of conditions, we focused first on what might inhibit or block STM. This problem was partially anticipated in 1900, according to McGaugh (7) who cited Muller and Pilzecker as having found that memory of newly learned information was disrupted by the of other information shortly after the original learning (8). This concept led us to test, in Hermissenda, whether STM recall (at 5 min) might be blocked simply by the input of additional information (i.e. extraneous sensory stimuli) if the latter were applied within the first 5 min after conditioning. The initial results of the blocking experiments, which showed that the simple sensory inputs blocking STM also blocked LTM, then led to the hypothesis that temporal consolidation of LTM could be detected by measuring when the blocking sensory input was no longer effective. Hermissenda (Sea Life Supply, Sand City, CA) were tested with 2 and 9 paired CEs for induction of STM and LTM. Conditioning events consisted of exposing the animals to 6 s of bright, white light (CS) explicitly paired with 4 s of strong orbital agitation (US) following a 2-s onset delay with an inter-trial interval of 1 min. Recall of the behavioral modification induced by associative conditioning was assessed by recording the animal's change in foot length when presented with 6 s of light alone. The conditioned response (CR) was foot contraction, the unconditioned response (UR) was foot elongation (9). Two paired conditioning events initiated behavioral recall after 5 min but not after 90 min; the LTM input of 9 pairings was recalled at both 5 and 90 min (Fig. 1A). The small and non-overlapping S.E.Ms for each point indicate statistical significance (P = <0.01, t = 3.18). After giving the animals the paired CS and US stimuli leading to STM, we tested two simple paradigms of blocking sensory stimuli. The first was a modification of the conditioning stimuli: dim orange light and very slow orbital rotation. The second blocking stimulus tested consisted of rotating the tray containing the animals upside down and, after 5 s, rotating it upright again (rotational block). Both experimental paradigms blocked STM and LTM (Fig. 1B). To determine the temporal specificity of LTM in Hermissenda, the following experiments were done. Animals were trained with 9 CEs, and the CR was measured at the usual 90 min. However, at selected time intervals (2, 25, 50, 55, 60, 65 min) post-conditioning, the animals were rotationally blocked. Control animals received only the 9 paired CEs. When the animals' behavior was plotted, a clear and decisive LTM consolidation interval in Hermissenda appeared; consolidation occurred between 55 and 60 min (Fig. 1C). Presentations of rotational blocking prior to 55 min totally blocked consolidation. However, the stimulus given after 60 had no blocking effects, and the animals demonstrated the CR. The consistency of and surprisingly little variability in the response among the majority of the animals indicated the robustness of the paradigm. When the data were analyzed with t-test and F-test statistics, they were found to be highly significant, whether compared between data points or to zero (P = <0.001, t = 15.24; F-value, inf). 182

Reciprocal inhibition of the AMPA and NMDA components of excitatory postsynaptic potentials in field CA1 of the rat hippocampus in vitro

The mutual effects of components of excitatory postsynaptic potentials (EPSP) induced by activation of glutamate receptors sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) were studied on living slices of rat hippocampus. Evoked responses were recorded in the radial layer (stratum radialis) in field CA1 after stimulation of collateral-commissural fibers. The contribution of the NMDA component to the total EPSP was altered by extracellular application of solutions containing different concentrations of magnesium. At low magnesium concentrations, when both components made significant contributions to EPSP, inhibition of one of the components by application of antagonists of the appropriate receptors led to increases in the area of the other component. Thus, the total magnitude of pharmacologically isolated components were significantly greater than the control response (for example, at 0.1 mM magnesium, the sum of the components was 340 +/- 120% of the control two-component EPSP (p < 0.01; N = 6). These results suggest that in controls, the AMPA and NMDA components of EPSP inhibit each other. The mutual inhibition of components may be an important factor affecting the conductivity and plastic properties of central glutamatergic synaptic pathways.

Selective suppression of forward and recurrent "rapid" inhibition by local application of picrotoxin in area CA1 of rat hippocampal slices.

Living slices of rat hippocampus were used to study the possibility of suppressing forward and recurrent "rapid" inhibition in area CA1 by local application of picrotoxin, an antagonist of ionotropic gamma-aminobutyric acid (GABAA) receptors. Application of picrotoxin to the apical dendrites increased the duration of focal potentials recorded in the radial layer (143.0 +/- 7.5%, n = 5; here and subsequently, results are presented as mean +/- error of the mean and n is the number of experiments) but had no effect on the population peak in the pyramidal layer (103.0 +/- 19.6%, n = 5). This is evidence for the existence of suppression of direct, but not of recurrent inhibition. Application of picrotoxin to the cell body layer, on the other hand, significantly increased the population peak (654.5 +/- 245.1%, n = 4) and provoked convulsive activity in neurons, demonstrating suppression of recurrent inhibition. Local application of picrotoxin was further used to study the question of how completely antagonists of glutamate ionotropic receptors sensitive to alpha-amino-3-hydroxy-S-methyl-4-isoxazole propionic acid (AMPA) suppress inhibition in solutions with low magnesium contents. This question is important for interpreting experimental data obtained from measurements of the components of excitatory postsynaptic potentials (EPSP), which depend on activation of ionotropic glutamate receptors sensitive to N-methyl-d-aspartic acid (NMDA). A number of studies have suggested that even at low concentrations, AMPA receptor antagonists suppress forward inhibition to such an extent that it has no significant effect on measurements of the NMDA component of EPSP. Our data do not contradict this suggestion.

Regulation of the NMDA component of EPSPs by different components of postsynaptic GABAergic inhibition: computer simulation analysis in piriform cortex.

Regulation of the NMDA component of EPSPs by different components of postsynaptic GABAergic inhibition: computer simulation analysis in piriform cortex. J. Neurophysiol. 78: 2546-2559, 1997. Physiological analysis in the companion paper demonstrated that gamma-aminobutyric acid-A (GABAA)-mediated inhibition in piriform cortex is generated by circuits that are largely independent in apical dendritic and somatic regions of pyramidal cells and that GABAA-mediated inhibitory postsynaptic currents (IPSCs) in distal dendrites have a slower time course than those in the somatic region. This study used modeling methods to explore these characteristics of GABAA-mediated inhibition with respect to regulation of the N-methyl--aspartate (NMDA) component of excitatory postsynaptic potentials. Such regulation is relevant to understanding NMDA-dependent long-term potentiation (LTP) and the integration of repetitive synaptic inputs that can activate the NMDA component as well as pathological processes that can be activated by overexpression of the NMDA component. A working hypothesis was that the independence and differing properties of IPSCs in apical dendritic and somatic regions provide a means whereby the NMDA component and other dendritic processes can be controlled by way of GABAergic tone without substantially altering system excitability. The analysis was performed on a branched compartmental model of a pyramidal cell in piriform cortex constructed with physiological and anatomic data derived by whole cell patch recording. Simulations with the model revealed that NMDA expression is more effectively blocked by the slow GABAA component than the fast. Because the slow component is present in greater proportion in apical dendritic than somatic regions, this characteristic would increase the capacity of dendritic IPSCs to regulate NMDA-mediated processes. The simulations further revealed that somatic-region GABAergic inhibition can regulate the generation of action potentials with little effect on the NMDA component generated by afferent fibers in apical dendrites. As a result, if expression of the NMDA component or other dendritic processes were enabled by selective block of dendritic inhibition, for example, by centrifugal fiber systems that may regulate learning and memory, the somatic-region IPSC could preserve system stability through feedback regulation of firing without counteracting the effect of the dendritic-region block. Simulations with paired inputs revealed that the dendritic GABAA-mediated IPSC can regulate the extent to which a strong excitatory input facilitates the NMDA component of a concurrent weak input, providing a possible mechanism for control of "associative LTP" that has been demonstrated in this system. Postsynaptic GABAB-mediated inhibition had less effect on the NMDA component than either the fast or slow GABAA components. Depolarization from a concomitant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) component also was found to have comparatively little effect on current through the NMDA channel because of its brief time course.

Impaired modulation of AMPA receptors by calcium-dependent processes in streptozotocin-induced diabetic rats

The mechanisms by which diabetes impairs cognitive function are not well-established. In the present study, we determined the electrophysiological and biochemical nature of disturbances in the mechanism of long-term potentiation (LTP) in diabetic rats. As previously reported, the administration of streptozotocin (STZ) was found to reduce the magnitude of LTP in the CA1 region of the hippocampus, while the same treatment did not interact with the capacity of the hippocampus to generate long-term depression induced by low-frequency stimulation. In addition, STZ treatment did not modify the component of excitatory postsynaptic potentials mediated by activation of the N-methyl- d-aspartate (NMDA) subtype of glutamate receptors, suggesting that NMDA receptor function remained intact in STZ-treated slices. At the biochemical level, the capacity of calcium to increase [ 3H]( RS)-α-amino-3-hydroxy-5-methylisoxazole propionic acid ( 3H-AMPA) binding to glutamate/AMPA receptors in rat brain tissue sections was markedly affected in most regions of the hippocampus of STZ-treated rats. Moreover, changes in 3H-AMPA binding properties elicited by both exogenous phospholipase A 2 and melittin, a potent activator of endogenous phospholipases, were also altered in synaptoneurosomes from diabetic rats. Taken together, the present data suggest that the loss of LTP maintenance in STZ-treated rats is more likely the result of disruption of calcium-dependent processes that are suspected to modulate postsynaptic AMPA receptors during synaptic potentiation. Understanding the biochemical factors participating in the impairment of AMPA receptor modulation might provide important clues revealing the very basis of memory deficits in diabetes.

Input patterns and pathways from the six semicircular canals to motoneurons of neck muscles. II. The longissimus and semispinalis muscle groups.

To reveal patterns of input from the six semicircular canals to motoneurons of various neck muscles and their relationship to the mechanical actions of individual neck muscles, patterns of input to neck motoneurons of the longissimus and the semispinalis muscle groups were investigated in the upper cervical spinal cord of anesthetized cats. Intracellular potentials were recorded from motoneurons of the longissimus muscle group (obliquus capitis superior muscle, OCS; splenius muscle, SPL; longissimus muscle, LONG) and the semispinalis muscle group (biventer cervicis muscle, BIV; complexus muscle, COMP), and effects of separate electrical stimulation of the six ampullary nerves on them were analyzed in each preparation. Neck motoneurons usually received convergent inputs from all of the six ampullary nerves, and motoneurons that supplied a particular muscle had a homogeneous pattern of input from the six ampullary nerves. Two different patterns of input were identified for motoneurons of these two muscle groups; one pattern for motoneurons of the longissimus muscle group and the other pattern for motoneurons of the semispinalis muscle group. Motoneurons of the OCS, the SPL, and the LONG muscles received excitation from the three contralateral ampullary nerves and inhibition from the three ipsilateral ampullary nerves. BIV and COMP motoneurons received excitation from the bilateral anterior canal nerves (ACNs) and the contralateral canal nerve (LCN) and inhibition from the bilateral posterior canal nerves (PCNs) and the ipsilateral LCN. Latencies of postsynaptic potentials (PSPs) evoked by stimulation of each of the six ampullary nerves indicated that the earliest component of excitatory PSPs (EPSPs) and inhibitory PSPs (IPSPs) was disynaptic in these motoneurons. However, trisynaptic IPSPs were evoked by stimulation of the contralateral PCN in a considerable number of BIV and COMP motoneurons. In OCS, SPL, and LONG motoneurons, all of the excitation from the contralateral and all of the inhibition from the ipsilateral ampullary nerves were mediated through the ipsilateral medial longitudinal fascicle (MLF). In BIV and COMP motoneurons, disynaptic excitation from the contralateral ACN and LCN and disynaptic inhibition from the ipsilateral LCN and bilateral PCNs were mediated through the ipsilateral MLF, whereas disynaptic excitation from the ipsilateral ACN was mediated through the ipsilateral lateral vestibulospinal tract. The patterns of semicircular canal input to neck motoneurons of these two muscle groups are related closely to the mechanical actions of the individual neck muscles and the optimal stimulus to the semicircular canals such that the connections will tend to stabilize head positions in response to head perturbations.

Suppression of long‐term potentiation in hippocampal slices by copper

Cu2+-ions are known to interfere with γ-aminobutyric acid (GABA)- and glutamate-operated ion channels from experiments with isolated neurons. Such actions are likely involved in the pathophysiology of Wilson's disease. We have now studied the effects of Cu2+ in the CA 1 region of hippocampal slices. Field excitatory postsynaptic potential (EPSP) slopes in the CA1 region were unaffected by 1 μM Cu2+ but were depressed by 10 μM (to 85%) and 100 μM (to 50%). A paired-pulse test revealed no difference in facilitation in the presence or absence of Cu2+, indicating a postsynaptic action. A late component of intracellularly registered EPSPs in Mg2+-free solution was also reduced by Cu2+. The N-methyl-D-aspartate (NMDA) component of the field EPSP, isolated by adding CNQX and bicuculline in Mg2+-free solution, was reduced to 69% of control by 1 μM and to 50% of control by 10 μM Cu2+. Long-term potentiation, evoked by 3 × 50 pulses at 100 Hz, 20 s interval amounted to 132 ± 11% 90 min after tetanization under control conditions but was absent in the presence of 1 μM Cu2+ in the bath. Thus low concentrations of copper can selectively reduce NMDA-mediated potentials and synaptic plasticity. Hippocampus 1997;7:666–669. © 1997 Wiley-Liss, Inc.

Suppression of long-term potentiation in hippocampal slices by copper.

Cu(2+)-ions are known to interfere with gamma-aminobutyric acid (GABA)- and glutamate-operated ion channels from experiments with isolated neurons. Such actions are likely involved in the pathophysiology of Wilson's disease. We have now studied the effects of Cu2+ in the CA1 region of hippocampal slices. Field excitatory postsynaptic potential (EPSP) slopes in the CA1 region were unaffected by 1 microM Cu2+ but were depressed by 10 microM (to 85%) and 100 microM (to 50%). A paired-pulse test revealed no difference in facilitation in the presence or absence of Cu2+, indicating a postsynaptic action. A late component of intracellularly registered EPSPs in Mg(2+)-free solution was also reduced by Cu2+. The N-methyl-D-aspartate (NMDA) component of the field EPSP, isolated by adding CNQX and bicuculline in Mg(2+)-free solution, was reduced to 69% of control by 1 microM and to 50% of control by 10 microM Cu2+. Long-term potentiation, evoked by 3 x 50 pulses at 100 Hz, 20 s interval amounted to 132 +/- 11% 90 min after tetanization under control conditions but was absent in the presence of 1 microM Cu2+ in the bath. Thus low concentrations of copper can selectively reduce NMDA-mediated potentials and synaptic plasticity.