Role of protein kinase C in modulation of excitability of CA1 pyramidal neurons in the rat.

Biochemical and in situ hybridization studies demonstrated that the levels of protein kinase C variants were significantly increased in the hippocampus of the experimental models of epilepsy in rats. In addition it has been demonstrated that protein kinase C plays an important role in modulating synaptic transmission in the hippocampus. We examined the effects of activating of protein kinase C on the excitability of CA1 pyramidal neurons and synaptic transmission, using whole-cell current-clamp and extracellular field potential recording techniques. Indolactam V (1 microM) a novel protein kinase C activator, increased the excitability of CA1 neurons acting at both pre- and post-synaptic sites. Indolactam V, acting postsynaptically, significantly reduced the threshold for initiation of action potential from -42+/-3.8 mV to -51+/-3.1 mV and selectively inhibited the slow afterhyperpolarizing potential. Indolactam V also altered the neuronal firing properties in response to prolonged depolarizing pulse by eliminating the spike frequency accommodation. Our data indicate that indolactam V potentiated both amplitudes of Shaffer-collateral stimulation evoked excitatory postsynaptic currents and disynaptically evoked inhibitory evoked postsynaptic currents. However, the potentiation of inhibitory evoked postsynaptic currents amplitudes was not observed after blockade of NMDA and AMPA/kainate currents suggesting it was due to excitatory activity driving inhibitory neurons. The results indicate that the potentiation of pharmacologically isolated excitatory postsynaptic currents (215% of control) and amplitudes of population spikes (290% of control) was due to action of indolactam V presynaptically since the agonist reduced the paired-pulse ratio and the potentiating effect was not blocked by dialyzing the postsynaptic neuron through the recording electrode with a specific protein kinase C inactivator calphostin C. These findings suggest that protein kinase C increases the amplitude of epileptiform activity by causing potentiation of excitatory synaptic transmission, increasing the excitability of postsynaptic neurons and reducing negative feed back provided by slow afterhyperpolarizing potential.

Changes in neuronal excitability and synaptic function in a chronic model of temporal lobe epilepsy.

Long-term potentiation and depression of glutamatergic synaptic responses are accompanied by an increased firing probability of neurons in response to a given excitatory input. This property, named excitatory postsynaptic potential/spike potentiation, has also been described in epileptic tissue and has pro-epileptic consequences. In this study, we show that excitatory postsynaptic potential/spike potentiation can be reversed in the kainic acid lesioned rat hippocampus, a chronic model of temporal lobe epilepsy. Simultaneous in vitro extracellular recordings in stratum radiatum and stratum pyramidale were performed in the CA1 area of the kainic acid lesioned rat hippocampal slices. Fifteen minutes, application of the K(+) channel blocker tetraethylammonium resulted in excitatory postsynaptic potential/spike potentiation (measured 90min after the start of the washout period) which could be reversed by subsequent low-frequency or tetanic stimuli. Excitatory postsynaptic potential/spike potentiation and its subsequent reversal by an electrical conditioning stimulus were found to have a N-methyl-D-aspartate receptor-independent component. Tetraethylammonium treatment also resulted in excitatory postsynaptic potential/spike potentiation of pharmacologically isolated N-methyl-D-aspartate receptor-mediated responses which could be reversed by subsequent low-frequency or tetanic stimuli. We conclude that excitatory postsynaptic potential/spike potentiation can be reversed in epileptic tissue, even in the absence of synaptic plasticity. These results suggest the presence of endogenous regulatory mechanisms which are able to decrease cell excitability.

Distribution of spontaneous currents along the somato-dendritic axis of rat hippocampal CA1 pyramidal neurons.

Excitatory and inhibitory pathways have specific patterns of innervation along the somato-dendritic axis of neurons. We have investigated whether this morphological diversity was associated with variations in the frequencies of spontaneous and miniature GABAergic and glutamatergic synaptic currents along the somato-dendritic axis of rat hippocampal CA1 pyramidal neurons. Using in vitro whole cell recordings from somata, apical dendrites and basal dendrites (for which we provide the first recordings) of CA1 pyramidal neurons, we report that over 90% of the spontaneous currents were GABAergic, <10% being glutamatergic. The frequency of spontaneous GABAergic currents was comparable in the soma and in the dendrites. In both somata and dendrites, the Na(+) channel blocker tetrodotoxin abolished more than 80% of the spontaneous glutamatergic currents. In contrast, tetrodotoxin abolished most dendritic (>90%) but not somatic (<40%) spontaneous GABAergic currents. Computer simulations suggest that in our experimental conditions, events below 40pA are electrotonically filtered to such a degree that they are lost in the recording noise. We conclude that, in vitro, inhibition is massively predominant over excitation and quantitatively evenly distributed throughout the cell. However, inhibition appears to be mainly activity-dependent in the dendrites whereas it can occur in the absence of interneuron firing in the soma. These results can be used as a benchmark to compare values obtained in pathological tissue, such as epilepsies, where changes in the balance between excitation and inhibition would dramatically alter cell behaviour.

Dendrites of classes of hippocampal neurons differ in structural complexity and branching patterns.

Dendrites of reconstructed hippocampal neurons were analyzed for morphometric, topologic, and fractal parameters (n = 32 quantities) to investigate neuronal groupings and growth characteristics with a common set of assumptions. The structures studied included CA1 and CA3 pyramidal cells, interneurons, and granule cells from young animals (71 cells in total). Most of the cells showed no characteristic fractal dimension; rather, the scaling relation could be well represented by a two-parameter fit, of which one parameter showed a significant difference between cell classes. Other significant quantities that differentiated cell classes were related to the complexity of the dendritic tree (number of branch points and maximal terminal branch order) and the cell's electrical properties such as the mean attenuation between the soma and terminals. Principal components analysis produced combined measures of only slightly greater discriminative power than the best individual measures, indicating that the elementary quantities capture most of the structural variation between hippocampal cell groups. Another finding was that for all cells the mean segment length increased with dendritic branch order, which is consistent with decreasing branching probability as a function of the path distance from the soma. Analysis of another set of CA1 pyramidal neurons from aged animals (n = 15; 22-24 months) showed only a few significant differences than those from young animals (n = 11; a subset of n = 71) of which the most important was a straightening of the paths between terminals and the soma. The quantities analyzed in these reconstructed hippocampal neurons may reflect both intrinsic neuronal characteristics and extrinsic influences. Hippocampal cell groupings (i.e., pyramidal cells as opposed to dentate granule cells and interneurons) were significantly differentiated by most parameters. These differences and parameter values may be critical for understanding and generating synthetic neuronal populations for modelling studies.

Reduced Mg2+ blockade of synaptically activated N-methyl-D-aspartate receptor-channels in CA1 pyramidal neurons in kainic acid-lesioned rat hippocampus.

Unilateral kainic acid lesion in the hippocampus caused a long-term change in the balance between excitatory and inhibitory drive onto CA1 pyramidal cells, making these cells hyperexcitable several weeks post-lesion. In this study, we have shown an enhanced N-methyl-D-aspartate receptor-mediated component in the excitatory synaptic transmission together with a reduced GABA(A) receptor-mediated inhibition in CA1 pyramidal cells one-week post kainic acid lesion. In these cells, pharmacologically isolated N-methyl-D-aspartate receptor-mediated whole-cell excitatory postsynaptic currents were significantly larger at negative holding potentials, and the voltage-dependence of N-methyl-D-aspartate receptor channels was shifted in the hyperpolarizing direction. The plot of relative conductance (g/gMax) shifted significantly (P<0.01) to more negative holding potentials by 19 mV (-28+/-4 mV in control slices and -47+/-4 mV in kainic acid slices) at the half maximal conductance point (g/gMax =0.5). This shift gives a larger N-methyl-D-aspartate receptor-mediated component in the excitatory synaptic transmission at resting membrane potentials (around -60 mV). The shifted voltage dependence is highly sensitive to extracellular Mg2+ ions. Moderate increases in [Mg2+]o from 1 mM to 2.6 mM more than compensated for the negative shift and effectively suppressed the population epileptiform bursting activity. Fitting the voltage dependence to an ionic block model revealed a higher dissociation constant of N-methyl-D-aspartate receptor channels for Mg2+ in kainic acid-lesioned slices (52 mM at 0 mV; 330 microM at -60 mV) than in control slices (7.7 mM at 0 mV; 93 microM at -60 mV). While a simple single site model adequately fitted the control data for [Mg2+]o at 1 mM and 2.6 mM, no consistent model of this form was found for the kainic acid-lesioned slices. These results revealed changed properties of N-methyl-D-aspartate receptor channels in the kainic acid-lesioned model of epilepsy. The reduced Mg2+ blockade of N-methyl-D-aspartate receptor channels contributed significantly to the epileptiform bursting activity.

An on-line archive of reconstructed hippocampal neurons.

We have developed an on-line archive of neuronal geometry to encourage the use of realistic dendritic structures in morphometry and for neuronal modeling, located at web address www.neuro.soton.ac.uk. Initially we have included full three-dimensional representations of 87 neurons from the hippocampus, obtained following intracellular staining with biocytin and reconstruction using Neurolucida. The archive system includes a structure editor for correcting any departures from valid branching geometry and which allows simple errors in the digitisation to be corrected. The editor employs a platform-independent file format which enforces the constraints that there should be no isolated branches and no closed loops. It also incorporates software for interconversion between the archive format and those used by various neuronal reconstruction and modelling packages. The raw data from digitisation software can be included in the archive as well as edited reconstructions and any further information available. Cross-referenced tables and indexes are updated automatically and are sorted according to a number of fields including the cell type, contributor, submission date and published reference. Both the archive and the structure editor should facilitate the quantitative use of full three-dimensional reconstructions of neurons from the hippocampus and other brain regions.

Molecular mechanisms that underlie structural and functional changes at the postsynaptic membrane during synaptic plasticity.

The synaptic plasticity that is addressed in this review follows neurodegeneration in the brain and thus has both structural as well as functional components. The model of neurodegeneration that has been selected is the kainic acid lesioned hippocampus. Degeneration of the CA3 pyramidal cells results in a loss of the Schaffer collateral afferents innervating the CA1 pyramidal cells. This is followed by a period of structural plasticity where new synapses are formed. These are associated with changes in the numbers and shapes of spines as well as changes in the morphometry of the dendrites. It is suggested that this synaptogenesis is responsible for an increase in the ratio of NMDA to AMPA receptors mediating excitatory synaptic transmission at these synapses. Changes in the temporal and spatial properties of these synapses resulted in an altered balance between LTP and LTD. These properties together with a reduction in the inhibitory drive increased the excitability of the surviving CA1 pyramidal cells which in turn triggered epileptiform bursting activity. In this review we discuss the insights that may be gained from studies of the underlying molecular machinery. Developments in one of the collections of the cogs in this machinery has been summarized through recent studies characterizing the roles of neural recognition molecules in synaptic plasticity in the adult nervous systems of vertebrates and invertebrates. Such investigations of neural cell adhesion molecules, cadherins and amyloid precursor protein have shown the involvement of these molecules on the morphogenetic level of synaptic changes, on the one hand, and signal transduction effects, on the other. Further complex cogs are found in the forms of the low-density lipoprotein receptor (LDL-R) family of genes and their ligands play pivotal roles in the brain development and in regulating the growth and remodelling of neurones. Evidence is discussed for their role in the maintenance of cognitive function as well as Alzheimer's. The molecular mechanisms responsible for the clustering and maintenance of transmitter receptors at postsynaptic sites are the final cogs in the machinery that we have reviewed. Postsynaptic densities (PSD) from excitatory synapses have yielded many cytoskeletal proteins including actin, spectrin, tubulin, microtubule-associated proteins and calcium/calmodulin-dependent protein kinase II. Isolated PSDs have also been shown to be enriched in AMPA, kainate and NMDA receptors. However, recently, a new family of proteins, the MAGUKs (for membrane-associated guanylate kinase) has emerged. The role of these proteins in clustering different NMDA receptor subunits is discussed. The MAGUK proteins are also thought to play a role in synaptic plasticity mediated by nitric oxide (NO). Both NMDA and non-NMDA receptors are highly clustered at excitatory postsynaptic sites in cortical and hippocampal neurones but have revealed differences in their choice of molecular components. Both GABAA and glycine (Gly) receptors mediate synaptic inhibition in the brain and spinal cord. Whilst little is known about how GABAA receptors are localized in the postsynaptic membrane, considerable progress has been made towards the elucidation of the molecular mechanisms underlying the formation of Gly receptors. It has been shown that the peripheral membrane protein gephyrin plays a pivotal role in the formation of Gly receptor clusters most likely by anchoring the receptor to the subsynaptic cytoskeleton. Evidence for the distribution as well as function of gephyrin and Gly receptors is discussed. Postsynaptic membrane specializations are complex molecular machinery subserving a multitude of functions in the proper communication between neurones. Despite the fact that only a few key players have been identified it will be a fascinating to watch the story as to how they contribute to structural and functional plasticity unfold.

Changes in dendritic structure and function following hippocampal lesions: correlations with developmental events?

Recovery after nervous system lesions may lead to partial re-institution of developmental schemes and processes. Here we review several of these proposed schemes, with the conclusion that though some processes may involve re-expression of embryonic phenotypes, there are many processes invoked during recovery from lesions that do not mirror developmental phenomena. The inability to fully revert to embryonic schemes because of adult phenotype may partially account for the decreased recovery observed in adults compared to that noted after lesions during development.

Pro-epileptic changes in synaptic function can be accompanied by pro-epileptic changes in neuronal excitability.

Repetitive sensory input, stroboscopic lights or repeated sounds can induce epileptic seizures in susceptible individuals. In order to understand the process we have to consider multiple factors. The output of a set of neurones is determined by the amount of excitatory synaptic input, the degree of positive feedback and their inherent electrical excitability, which can be modified by synaptic inhibition. Recent research has shown that it is possible to separate these phenomena, and that they do not always behave in unison.

Reversal of excitatory postsynaptic potential/spike potentiation in the CA1 area of the rat hippocampus.

In the CA1 area of the hippocampus, low frequency and tetanic conditioning stimuli are known to trigger long-term depression and potentiation of synaptic responses respectively and to produce irreversible excitatory postsynaptic potential/spike potentiation, i.e. an increase of the probability of discharge of the neurons. Using simultaneous extracellular recordings in stratum radiatum and stratum pyramidale in the CA1 area of the rat hippocampus, brief application of the K+ channel blocker tetraethylammonium resulted both in long-term potentiation of synaptic responses and in excitatory postsynaptic potential/spike potentiation that could be reversed by subsequent low frequency or tetanic stimuli. Excitatory postsynaptic potential/spike potentiation and its subsequent reversal by an electrical conditioning stimulus were found to have an N-methyl-D-aspartate receptor-independent component. We conclude that the reversal of excitatory postsynaptic potential/spike potentiation can occur and that it does not require the induction of long-term modification of synaptic responses.

Excitatory synaptic site heterogeneity during paired pulse plasticity in CA1 pyramidal cells in rat hippocampus in vitro.

1. The properties of individual excitatory synaptic sites onto adult CA1 hippocampal neurons were investigated using paired pulse minimal stimulation and low noise whole-cell recordings. Non-NMDA receptor-mediated synaptic responses were isolated using a pharmacological blockade of NMDA and GABAA receptors. Amongst the twenty-five stationary ensembles there were twelve showing paired pulse potentiation, two showing paired pulse depression and eleven with no significant net change. The signal-to-noise ratio averaged 4.5:1. There was no correlation between the amplitude of the first and second responses after separation of failures: the percentage of failures averaged 33.6% for the conditioning pulse and 31.7% for the test pulse. 2. Site-directed Bayesian statistical analysis was developed to predict the likely number of activated synapses, synaptic response amplitudes, probability of release and intrinsic variation at each individual synaptic site. Extensive simulations showed the usefulness of this model and defined appropriate parameters. These simulations demonstrated only small errors in estimating parameters of data sets with a small number of sites (< 10) and similar characteristics to the physiological data sets. 3. Physiological ensembles showed between one and three synaptic sites, which exhibited a wide range of values for release probability (0.03-0.99), synaptic amplitudes (1.46-16.8 pA; approximately 62% coefficient of variation between sites) and intrinsic variation over time (approximately 36%). Paired pulse plasticity occurred primarily from alterations in the release probabilities but a few ensembles also showed small changes in site amplitude. Initial release probability correlated negatively with the degree of paired pulse potentiation. Whilst it was possible to use simple assumptions regarding site homogeneity (such as required for a binomial process) for 48% (12 out of 25) of the data sets, the Bayesian analysis was necessary to reveal the complex changes and heterogeneity that occurred in the other 52% of the data sets. The Bayesian site analysis robustly indicated the presence of considerable site heterogeneity, significant intrinsic site variation over time and changes in parameters at individual synaptic sites with plasticity.

Model of spatio-temporal propagation of action potentials in the Schaffer collateral pathway of the CA1 area of the rat hippocampus.

There is a sharp contrast between the profuse in vivo axonal arborization of CA3 pyramidal cells in the CA1 area and the low probability of finding pairs of connected CA3-CA1 pyramidal cells in vitro. These anatomical differences contribute to a connectivity argument for discrepancies between electrophysiological data recorded in vitro and in vivo. In order to investigate this issue, we have developed a realistic computer model of the Schaffer collateral pathway of the hippocampus and analyzed the spatio-temporal distribution of action potentials along this pathway following three different types of electrical test stimulus. Direct activation of mossy fibers, CA3 pyramidal cells and focal stimulation of CA1 stratum radiatum were investigated. The parameters of the model were selected from available biological data. Spikes in Schaffer collaterals were followed from their onset in the CA3 pyramidal cell initial segment to the last order branches of their axonal tree in two types of configuration: the whole hippocampus and the slice configuration. The anatomical and electropysiological characteristics of the mossy fibre and Schaffer collateral pathways were found to impose strong constraints on the spatio-temporal distribution of action potentials in the CA1 area. Specific projection zones are determined by the spatial localization of the emitting CA3 pyramidal cells. Their position also defines precise time windows during which some CA1 projection zones receive a large number of correlated signals. Moreover, the variability of the delay at the mossy fibre/CA3 pyramidal cell synapse seems to provide the CA1 projection zones with a background level of excitation. Finally, we show how the patterns of activation obtained in the whole hippocampus are different from those obtained in the slice.

Synaptic release rather than failure in the conditioning pulse results in paired-pulse facilitation during minimal synaptic stimulation in the rat hippocampal CA1 neurones.

In this paper we report our observations of the relationship of paired-pulse facilitation (PPF) with synaptic release or release failure at small numbers of synaptic sites. Minimal stimulation protocols were employed to enable the activation of only one or a few axons which synapse onto CA1 pyramidal cells in the hippocampus. Excitatory postsynaptic currents (EPSCs) in response to paired stimulation were measured. On the analysis of the data, we examined the effects of failure and synaptic release on PPF, and found that PPF was observed as a decrease in failures of synaptic release in response to test stimuli which were preceded by conditioning stimuli that evoked synaptic release. The test-pulse failure rate following conditioning pulse failures was indistinguishable from the overall conditioning pulse failure rate. It is postulated that the mechanism of paired-pulse facilitation is presynaptic and associated with successful synaptic release in response to the conditioning stimulus.

A role for synaptic and network plasticity in controlling epileptiform activity in CA1 in the kainic acid-lesioned rat hippocampus in vitro.

1. Stimulation of the surviving afferents in the stratum radiatum of the CA1 area in kainic acid-lesioned hippocampal slices produced graded epileptiform activity, part of which (> 20%) involved the activation of N-methyl-D-aspartate (NMDA) receptors. There was also a failure of synaptic inhibition in this region. In this preparation, we have tested the effects of low-frequency stimulation (LFS; 1 Hz for 15 min) on synaptic responses and epileptiform activity. 2. LFS resulted in long-term depression (LTD) of excitatory synaptic potentials (EPSPs), long-term decrease of population spike amplitudes (PSAs) and EPSP-spike (E-S) potentiation. Evoked epileptiform activity was reduced but neurons had a higher probability of discharge. LTD could be reversed by subsequent tetanic stimulation whereas E-S dissociation remained unchanged. Synaptic and network responses could be saturated towards either potentiation or depression. However, E-S potentiation was maximal following the first conditioning stimulus. 3. NMDA receptor-mediated responses were pharmacologically isolated. LFS resulted in LTD of synaptic responses, long-term decrease of PSAs and E-S depression. These depressions could not be reversed by subsequent tetanic stimulation. alpha-Amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) and NMDA receptor-mediated responses were then measured in isolation before and following conditioning stimuli. LFS was shown to simultaneously produce LTD of AMPA and NMDA receptor-mediated responses. E-S potentiation of the AMPA component and E-S depression of the NMDA component occurred coincidentally. 4. LTD of AMPA and NMDA receptor-mediated responses were shown to be NMDA dependent. In contrast, E-S potentiation and depression occurred even when NMDA receptors were pharmacologically blocked. 5. These findings indicate that synaptic responses could be modified bidirectionally in the CA1 area of kainic acid-lesioned rat hippocampus in an NMDA receptor-dependent manner. However, E-S dissociations were independent of the activation of NMDA receptors, hinting at mechanisms different from those of synaptic LTD. We suggest that changes in E-S coupling were caused by a modification of the firing threshold of the CA1 pyramidal neurons. Furthermore, the firing mechanisms controlling NMDA and AMPA receptor-mediated network activity appeared to be different. The possible use of LFS applied to the hippocampus as a clinical intervention to suppress epileptiform activity is discussed.

Pre-exposure to subtoxic levels prevents kainic acid lesions in organotypic hippocampal slice cultures: effects of kainic acid on parvalbumin-immunoreactive neurons and expression of heat shock protein 72 following the induction of tolerance.

The effects of kainic acid on the survival of principal neurons and parvalbumin-immunoreactive (PARV-IR) neurons, and on the expression of heat shock protein 72 immunoreactivity (HSP72-IR) were investigated in organotypic hippocampal slice cultures. Untreated cultures displayed an organotypic organization and the development and morphology of PARV-IR neurons in the hippocampus paralleled that reported to occur in vivo, with the exception of the hilar region of the dentate gyrus which exhibited a marked lack of PARV-IR neurons. No constitutive expression of HSP72 was found in untreated cultures. The lesion of CA3 neurons and the reduction in numbers of PARV-IR neurons in both CA3 and CA1 after chronic exposure to 5 microM kainic acid were similar to those reported to occur in vivo. Exposure to 1 microM doses of kainic acid resulted in a widespread appearance of HSP72-IR and the induction of tolerance to a previously toxic dose of kainic acid. These results suggest the presence of endogenous neuroprotective mechanisms, activated by a stress response which induces HSP72, and is reminiscent of the induced tolerance reported to occur after a mild ischaemic insult.

Hippocampal NPY neurons project to the fascia dentata in organotypic cultures.

The distribution of neuropeptide Y immunoreactive (NPY-ir) neurons in organotypic cultures of hippocampi from neonates was compared to that seen in adult rats. In addition to the known NPY-ir neurons in the hippocampus proper and in the hilus of the fascia dentata, isolated, large, multipolar, NPY-ir neurons were observed in the subiculum and in areas CA1 and CA3. Their axons projected into stratum radiatum of the hippocampus proper and into the molecular layers and hilus of the fascia dentata where they branched profusely. These NPY-ir neurons were regularly distributed throughout the septo temporal extent of the hippocampus and were present in both neonates and adult hippocampi. The hilar NPY-ir neurons have always been considered the source of the NPY-ir plexus in the outer molecular layer of the dentate gyrus. However, our results show that there is also a contribution from the NPY-ir neurons in the hippocampus proper.

Expression of EPSP/spike potentiation following low frequency and tetanic stimulation in the CA1 area of the rat hippocampus.

Low frequency stimulation (LFS, 1 Hz for 15 min) has been shown to produce an NMDA receptor dependent homosynaptic long-term depression (LTD) of synaptic potentials in the CA1 area of the rat hippocampus. Here we describe experiments aimed at characterizing EPSP/spike (E/S) coupling associated with this form of LTD. Our data show that following LFS neurons have a higher probability of synchronous discharge in response to a population EPSP of fixed slope (E/S potentiation). This E/S potentiation was not significantly enhanced by a tetanic stimulation. When the protocol was reversed, that is, starting with a tetanic stimulus, E/S potentiation was observed which was unaffected by a subsequent LFS. Saturating these synaptic responses to either a maximal or a minimal value produced similar effects on E/S coupling. E/S depression was never encountered. Finally, we found that the expression of E/S potentiation did not require the activation of NMDA receptors. These data suggest that at the level of a local neuronal network in the CA1 area, LFS is not a very powerful tool since the synaptic depression is associated with a potentiation of the population response of these neurons. Furthermore, the expression of E/S dissociation seems different from that of homosynaptic long-term potentiation and LTD.

Simultaneous expression of excitatory postsynaptic potential/spike potentiation and excitatory postsynaptic potential/spike depression in the hippocampus.

Tetanic stimulation of afferents in the stratum radiatum of the CA1 area of the rat hippocampus results in long-term potentiation of excitatory synaptic responses in pyramidal cells. Previous studies have reported a greater increase in the population spike amplitude following the induction of long-term potentiation than could be accounted for by the increase of the slope of the population excitatory postsynaptic potential. Two hypotheses have been proposed to explain this phenomenon (called excitatory postsynaptic potential/spike potentiation): a modification of the firing threshold and/or a modification of the inhibitory drive. Previous studies have not, however, addressed the question of possible changes in spike threshold in association with long-term depression. This paper examines whether the concomitant long-term potentiation of pharmacologically isolated N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potentials, reported previously, is also associated with a change in spike threshold. When the amplitude of the population spike is plotted as a function of the slope of the population excitatory postsynaptic potential (excitatory postsynaptic potential/spike curve), excitatory postsynaptic potential/spike potentiation (depression) is seen as a shift of the excitatory postsynaptic potential/spike curve to the left (right) following a conditioning stimulus. In this study, using kainic acid lesioned hippocampus, we have shown that tetanic stimulation produced excitatory postsynaptic potential/spike potentiation of the control synaptic response and excitatory postsynaptic potential/spike depression of the isolated N-methyl-D-aspartate receptor-mediated responses.

Simultaneous expression of long-term depression of NMDA and long-term potentiation of AMPA receptor-mediated synaptic responses in the CA1 area of the kainic acid-lesioned hippocampus.

This study investigates the plasticity of the excitatory synapses in an experimental model of epilepsy, the kainic acid-lesioned rat hippocampus. Stimulation of afferents in the CA1 area of lesioned hippocampi produced an epileptiform burst of action potentials, with an underlying synaptic potential composed of mixed alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA; 80%) and N-methyl-D-aspartate (NMDA; 20%) receptor-mediated components. Tetanic stimulation yielded a long-term potentiation (LTP) of the mixed AMPA/NMDA receptor-mediated population excitatory postsynaptic potentials. However, the same type of tetanus resulted in a long-term depression (LTD) of pharmacologically isolated NMDA receptor-mediated responses. This LTD occurred independently of the antagonism of AMPA receptors. This suggests that tetanic stimulation produced LTP of AMPA and LTD of NMDA receptor-mediated responses simultaneously. Finally, both LTP and LTD were shown to be NMDA dependent. This property has profound functional implications for the control of excitatory networks in temporal lobe epilepsy.

Plasticity of AMPA and NMDA receptor-mediated epileptiform activity in a chronic model of temporal lobe epilepsy.

We have investigated the consequences of tetanic stimulation on epileptiform activity mediated by NMDA and AMPA receptors in an experimental model of human temporal lobe epilepsy. Recordings were performed in the CA1 area of the hippocampus one week following intracerebroventricular injection of kainic acid. Data presented here show that, after tetanic stimulation, there was a long-term increase in the amplitude of the population spikes associated with the epileptiform burst. This activity was triggered by the simultaneous activation of both NMDA and AMPA receptors. However, whilst the pharmacologically isolated AMPA component of this burst underwent long-term enhancement, the NMDA component underwent a long-term decrease in amplitude. These data suggest that in this chronic model of epileptiform activity, there is long-term potentiation of excitatory mediated events regulated primarily by AMPA receptors. Furthermore, the slow time course of the NMDA receptor-mediated synaptic conductances was responsible for prolonging the duration of the epileptiform bursts. However, the powerful depression of NMDA receptor-mediated events following tetanic stimulation suppressed the normally large potentiation of the overall response. Thus although it has been suggested that the NMDA receptor-mediated synaptic events contribute to the epileptogenic properties of the neocortex and hippocampus, this evoked depression may act as an intrinsic anticonvulsant mechanism.