An analysis of the increase in granule cell excitability accompanying habituation in the dentate gyrus of the anesthetized rat

Repeated low-frequency stimulation of the perforant path results in a decrement in the population EPSP and population spike recorded in the hilus of the dentate gyrus. The EPSP decrement is accompanied, however, by an increase in the population spike height/population EPSP slope relation, suggesting that an increase in granule cell excitability also occurs. The present experiments explored the mechanisms of this apparent increase in excitability using standard field potential recording techniques to assess perforant path input/output curves in rats anesthetized with sodium pentobarbital. Low-frequency homosynaptic stimulation (512 pulses, 1 Hz) of the perforant path resulted in a decreased spike threshold and overall shift to the left of the function relating population spike height to EPSP slope. These changes were consistently produced, even when granule cell discharge was inhibited by conditioning stimulation of the contralateral hilus. On the other hand, low-frequency heterosynaptic (lateral perforant path) or antidromic (mossy fiber) driving of the granule cells only slightly increased the medial path spike/EPSP relation, and did not alter the spike threshold. The excitability shift accompanying habituation was qualitatively different from that associated with long-term potentiation, but these shifts did not summate. The interpretation which best explains these various results is that granule cell excitability is increased during low-frequency perforant path stimulation by a process of disinhibition, caused by habituation of perforant path excitatory synaptic drive onto feed-forward inhibitory interneurons.     

Kainic acid and penicillin: Differential effects on excitatory and inhibitory interactions in the CA1 region of the hippocampal slice

The effects of kainic acid (KA, 0.05-1.0 microM), and penicillin (PN, 3.4 mM) were studied in the CA1 region of rat hippocampal slices. Three components of the overall input/output function were taken: (1) the amplitude of the presynaptic compound action potential (prevolley) vs stimulation current applied to Schaffer collaterals, (2) the magnitude of the focally recorded synaptic potential (population EPSP) vs prevolley amplitude; and (3) the amplitude of the focally recorded population spike vs population EPSP magnitude. Recurrent inhibition was measured using the antidromic-orthodromic paired pulse method. KA caused a significant and reversible enhancement of all 3 component input/output functions while having no effect on paired pulse inhibition. PN caused a left shift in the EPSP-population spike relationship and decreased or abolished paired pulse inhibition; the other two measures of excitability were not changed. These results suggest that PN and KA differ fundamentally in the mechanisms by which they produce seizures: PN by removing inhibition while not affecting neuronal excitability per se; KA by exerting a generalized excitatory effect on neural membranes and on synaptic function while leaving recurrent inhibition unchanged.     

Differential effects of pentobarbital and ether on the synaptic transmission of the hippocampal CA1 region in the rat

The effect of ether and sodium pentobarbital on the synaptic transmission of the hippocampal CA1 region was studied in chronically implanted rats. Animal behavior, EEG, and the average evoked potentials (AEPs) following electrical stimulation of the alveus or the stratum radiatum in the CA1 region were recorded. Components of the AEPs, interpreted previously as generated by population excitatory postsynaptic potentials (EPSPs), population inhibitory postsynaptic potentials (IPSPs) (Leung 1979a, b, c) or population postsynaptic spikes (Andersen et al. 1971), were differentially sensitive to ether or pentobarbital. Ether reduced the population EPSPs and population spike evoked at all intensities tested (1-4 X threshold); the population IPSP was slightly enhanced at intermediate stimulus intensities. Pentobarbital suppressed the population EPSP evoked by alvear stimulation but not that by radiatum stimulation, reduced the population spike and greatly enhanced and prolonged the population IPSP evoked at low stimulus intensities. At high stimulus intensities, the IPSP was interpreted to be smaller after pentobarbital but neuronal output from the hippocampal CA1 region, as seen from the evoked population spike, remained attenuated. It is concluded that ether and pentobarbital both suppress hippocampal neuronal excitability but the effect of anesthesia differs for different anesthetics, for different synapses and for different levels of activity in the input fibers.     

The effects of cooling and rewarming on the neuronal activity of pyramidal neurons in guinea pig hippocampal slices

To investigate the reversibility of neuronal functions during deep and mild hypothermia, we have examined changes in membrane properties of pyramidal neurons of the CA3 region of hippocampal slices during cooling and rewarming (8 approximately 37 degrees C) of the perfusion medium. Hypothermia reduced the excitatory postsynaptic potential (EPSP) slope in a temperature dependent manner, but the EPSP amplitude was enhanced transiently between 30 and 25 degrees C. In observing spikes generated by either orthodromic stimulation or by direct intracellular current injection, the critical threshold for spike generation was decreased transiently at a temperature of 30 degrees C. In addition, the numbers of spikes were increased transiently regardless of the progressive prolongation of spike duration and latency with cooling. The resting membrane potential was stable from 37 to 20 degrees C. However, this potential showed a depolarizing shift at 15 degrees C. The neuronal activities, including membrane properties, recovered fully when the temperature was raised to 35 degrees C even from a low of 15 degrees C. In addition, field population spikes (PS) recorded in the pyramidal cell layer showed a complete reversibility after long-term severe hypothermia (8 degrees C). These results suggest that synaptic function, neuronal excitability and membrane properties maintain reversibility during deep hypothermia, as well as in mild hypothermia.     

Postischemic synaptic physiology in area CA1 of the gerbil hippocampus studied in vitro

After transient forebrain ischemia in the Mongolian gerbil, CA1b hippocampal pyramidal cells degenerate during a period of 2-4 d. We tested the hypothesis that this delayed neuronal death is preceded by excessive synaptic excitation. Hippocampal slices were prepared from gerbils that had been subjected to a 5 min occlusion of both common carotid arteries. Input/output curves demonstrated enhancement of the initial slope of the Schaffer collateral-commissural focally recorded EPSP at all stimulus currents between 5 and 10 hr after the ischemic insult. The duration of the focally recorded EPSP also increased. At the same time, the excitability of the CA1b pyramidal cells decreased. Thus, the EPSP brought fewer pyramidal cells to threshold than the same size EPSP in control slices. During the first 14 hr after ischemia, the antidromic population spike remained unaffected. By 24 hr after ischemia, however, the focally recorded EPSP and both orthodromic and antidromic population spikes were markedly depressed, and they declined further over the next 2 d. No recovery was detected. In the same slices, transient ischemia only mildly and reversibly affected the response of dentate granule cells to perforant path stimulation and did not affect their response to antidromic stimulation. Hippocampal slices adjacent to those used for electrophysiological recording were analyzed histologically. Examination of somatic argyrophilia confirmed that CA1b pyramidal cells suffered delayed neuronal death, whereas dentate granule cells remained intact. Pyramidal cell argyrophilia was, however, not detected until 2 d after these neurons had become virtually inexcitable. We conclude that CA1b pyramidal cells begin to lose electrophysiological function well before definite morphological signs of degeneration become visible. The observation of enhanced excitatory transmission 5-10 hr after reperfusion is consistent with the idea that delayed ischemic neuronal death results, at least in part, from excessive excitation.     

Identification and characterization of striatal cell subtypes using in vivo intracellular recording in rats: II. Membrane factors underlying paired-pulse response profiles

Two subtypes of neurons in the striatum have been defined on the basis of their different response patterns to paired-impulse stimulation of corticostriatal afferents, with type I cells showing a longer spike latency, facilitation at short intervals, and inhibition at long intervals, and type II cells defined by the facilitation occurring at long interstimulus intervals. Nevertheless, the companion report has shown that this distinction of cell types cannot be accounted for by differences in the basic physiological properties of these cells, but instead is likely to be due to differences in their synaptic connectivity. The experiments performed in this study were directed at examining in detail the membrane factors and synaptic responses that may contribute to these distinct response patterns. When pairs of stimuli were delivered to the corticostriatal fibers at 10-30 ms interstimulus intervals, the EPSPs elicited in type I neurons exhibited a temporal summation, resulting in a facilitation of spike firing to the second stimulus relative to the first. In contrast, type II cells showed decreased EPSP amplitude at short intervals, and in cells showing a short-interval inhibition, there was a significant increase in spike threshold (+5.3 ± 1.4 mV) during the second response. All type II neurons recorded with KCl-filled microelectrodes showed short-interval facilitation with little or no change in spike threshold. Although the use of KCI electrodes did not alter the facilitation at short intervals in type I neurons it did increase the rate of rise of the EPSP, causing spikes to be triggered at a latency similar to that of type II cells. Paired stimuli delivered at 75–150 ms interstimulus intervals showed inverse effects on type I and type II cells with respect to the probability of spike firing. In type I cells, the evoked EPSP was followed by a long-latency membrane hyperpolarization that prevented the second EPSP from reaching spike threshold. In contrast, the smaller-amplitude hyperpolarization evoked in type II cells enabled the second stimulus to activate an EPSP at the same membrane potential as the first stimulus, resulting in a facilitation of spiking. Therefore, despite the similarity in the basic physiological properties of type I and type II cells, the differences in their spike latencies and paired impulse response profiles appear to be dependent on the timing of their GABAergic inhibition at short intervals: A GABA-mediated conductance change occurs simultaneously with the EPSP in type I cells leading to a delay in triggering the evoked spike, whereas a later-developing GABA conductance change in type II cells results in an inhibition of spiking at short intervals. In contrast, the pronounced long-duration membrane hyperpolarization of type I cells appears to underlie the inhibition of spiking at long intervals, whereas in the type II cells the GABA-mediated decrease in cell excitability necessitated the use of larger-amplitude stimulation pulses to reach threshold with respect to the first stimulus, resulting in a higher probability of spike discharge to the second stimulus at long intervals. © 1994 Wiley-Liss, Inc.     

Decreases in excitatory synaptic transmission and increases in recurrent inhibition in the rat dentate gyrus after transient cerebral ischemia

Excitatory transmission along the perforant path from the entorhinal cortex to the granule cells of the dentate gyrus was evaluated two days after 10 min of transient cerebral ischemia in the rat. The amplitude of the population spike, and the amplitude and the initial slope of the population excitatory postsynaptic potential (EPSP) evoked by the perforant path stimulation were measured across a range of stimulus intensities, and were compared with control values. Inhibitory interactions were evaluated using the paradigm of paired pulse stimulation, comparing the amplitude of the population spike evoked by the second pulse of a pair to the initial spike. The maximal values of the initial slope of the population EPSP and the population spike were reduced in the ischemic group. Also, the extent of paired pulse inhibition was greater in the ischemic group. These results suggest that: (1) excitatory synaptic transmission along the perforant path is impaired in the postischemic period, (2) inhibition of the dentate granule cells is enhanced in this period. These results are not consistent with the hypothesis that there is a hyperactivation of the tri-synaptic circuit in the chronic postischemic period that accounts for the excitotoxic death of CA1 neurons.     

Enduring suppression of hippocampal long-term potentiation following traumatic brain injury in rat

This study investigated changes in synaptic responses (population spike and population EPSP) of CA1 pyramidal cells of the rat hippocampus to stimulation of the Schaffer collateral/commissural pathways 2-3 h after traumatic brain injury (TBI). TBI was induced by a fluid percussion pulse delivered to the parietal epidural space resulting in loss of righting responses for 4.90-8.98 min. Prior to tetanic stimulation, changes observed after the injury included: (1) decreases in population spikes threshold but not EPSP thresholds; (2) decreases in maximal amplitude of population spikes as well as EPSPs. TBI also suppressed long-term potentiation (LTP), as evidenced by reductions in post-tetanic increases in population spikes as well as EPSPs. Since LTP may reflect processes involved in memory formation, the observed suppression of LTP may be an electrophysiological correlate of enduring memory deficits previously demonstrated in the same injury model.     

Observations of synaptic efficacy and paired-pulse facilitation in area CA1 of hippocampal slices from coriaria lactone-kindled rats.

The changes of population spike(PS)/population excitatory postsynaptic potential (EPSP) slope relationship and paired-pulse facilitation (PPF) were primarily investigated with extracellular recording in stratum pyramidale to stimulation of Schaffer collaterals in CA1 region of hippocampal slices from coriaria lactone (CL)-kindled and control rats. The results were as follows: (1) neither spontaneous nor evoked epileptiform bursts were found in all hippocampal slices from CL-kindled and control rats; (2) the synaptic efficacy, expressed by the ratio of PS/EPSP slope, at low stimulation intensity ranging from 10-30% of its maximum was significantly increased on CL-kindled rats (P less than 0.05); and (3) although PPF was found in all slices, the PPF strength only at stimulation intensity of 10 and 20% of maximum was augmented remarkably in CL-kindled rats (P less than 0.002 and 0.024, respectively). According to the results from our previous work, we suggested that the increment of PS/EPSP slope ratio and PPF strength at low stimulation intensity may result from the potentiation of excitatory synaptic activity or/and the change of intrinsic excitability of pyramidal neurons.     

Effect of low glucose concentration on synaptic transmission in the rat hippocampal slice

Severe hypoglycemia in vivo is known to slow down the EEG, then to produce complete electrical silence in the brain. To find out why low glucose concentrations reduce electrical activity, synaptic transmission from Schaffer collateral/commissural fibers to CA1 pyramidal cells in the submerged rat hippocampal slice was investigated using extracellular recording techniques. Superfusion for 30 min with 1 mM glucose reversibly reduced population spike amplitude, without affecting the size of the presynaptic volley and the slope of the field EPSP. Lower glucose concentrations also affected the EPSP, although to a lesser extent than the population spike. Antidromic population spikes were not decreased by low glucose. Depolarization with 8-10 mM K+ reduced both presynaptic volley amplitude and EPSP, but enhanced the population spike, an effect clearly different from that of low glucose. The slope of the input/output curve between presynaptic volley and EPSP remained unaltered in 1 mM glucose but the slope between EPSP and population spike was reduced by about 50%. Results suggest that low glucose concentrations interrupt synaptic transmission by reducing, but not abolishing, the excitability of pyramidal cells.     

Field potential evidence for long-term potentiation of feed-forward inhibition in the rat dentate gyrus

Trains of high-frequency stimulation to the perforant path cause (i) long-term potentiation (LTP) of the population excitatory post-synaptic potential (EPSP), (ii) a lasting increase in the population spike, and (iii) a lasting alteration of the relationship between the EPSP and population spike (E-S relationship), consisting of a decreased x-intercept and decreased slope of the linear regression. To compare the thresholds of these changes, we applied a series of trains, increasing in duration from below LTP threshold. The EPSP potentiated with about the same low threshold as the reduction in E-S slope, whereas the reduction in E-S x-intercept required longer trains. In the second experiment, LTP of the EPSP was reduced by concurrent high-frequency stimulation of the commissural input and a lasting reduction of the population spike height was observed. In a third experiment, picrotoxin, an antagonist of gamma-aminobutyric acid (GABA)-mediated inhibition, blocked the decrease in slope of the E-S relationship which normally accompanies LTP. These results imply that perforant path/granule cell LTP is normally accompanied by long-term potentiation of a feed-forward inhibitory pathway which may involve interneurones.     

Long-term potentiation of the perforant path-granule cell synapse in the rat hippocampus.

When the entorhinal cortex is electrically stimulated, a monosynaptic evoked potential is produced in the ipsilateral hippocampus. Twenty-four hours after a 120-pulse stimulation train, the response to a single test pulse was found to be increased. Stimulation trains presented at a rate of 1/day had a cumulative effect on both the population EPSP and spike components of the evoked potential, and the potentiation so produced lasted at least 12 days. In a few cases, retested 2 months after the last stimulation train, the population EPSP was found to be still highly potentiated while the population spike had declined to initial levels. The most reliable results and largest potentiation were obtained with diphasic stimulation trains of 10 Hz or greater, though some changes were observed even with very low frequencies (0.2 Hz). The results imply that the efficiency of synaptic transmission in the perforant path-granule cell synapse can be modified.     

Mechanisms of long-term potentiation: EPSP/spike dissociation, intradendritic recordings, and glutamate sensitivity

Synaptic efficacy is modified following a brief train of high-frequency stimulation (HFS) to a cell's afferent fibers (long-term potentiation; LTP). An alteration in the postsynaptic response to endogenous neurotransmitter, as a result of an increase in the number of postsynaptic receptors, has been proposed (Baudry and Lynch, 1980). We tested this hypothesis in the CA1 hippocampus by intracellularly recording the postsynaptic response to localized application of glutamate before and after induction of LTP. When LTP was produced, there was no corresponding change in neuronal sensitivity to glutamate application. These findings are not consistent with the hypothesis that HFS of fibers in CA1 stratum radiatum induces an increase in the number of postsynaptic glutamate receptors in CA1 pyramidal cells. Previous reports concerning LTP have indicated a dissociation between the degree of potentiation in the population EPSP and population spike. Simultaneous recordings of the CA 1 population EPSP and population spike in hippocampal slices confirmed that the degree of potentiation of the population spike was not predicted by the degree of potentiation in the population EPSP. Intradendritic impalements were obtained to more accurately assess changes in the intracellular EPSP following HFS. When the population EPSP was potentiated, there was also a potentiated intradendritic EPSP. When the population spike was potentiated following HFS, however, the intradendritic EPSP was often unchanged; in the same cell, there was an increased probability of action potential discharge to stimulation which was originally (i.e., pre-HFS) subthreshold for spike initiation. These results indicate that the EPSP (intracellular or extracellular) may be potentiated following HFS, but this potentiation is not a prerequisite for, or a correlation of, potentiation in the population spike. Furthermore, these findings suggest that LTP is composed of 2 independent components--a synaptic component and an EPSP-to-spike coupling component.     

Induction of long-term depression and potentiation by low- and high-frequency stimulation in the dentate area of the anesthetized rat: magnitude, time course and EEG

We investigated the possible importance of stimulus train frequency for the induction and magnitude of long-term synaptic plasticity in the perforant path-granule cell pathway. Under the same experimental conditions, low- (15 Hz) or high-frequency (400 Hz) stimulation could elicit a profound long-term depression (LTD), or typical long-term potentiation (LTP), of the population spike amplitude, excitatory postsynaptic potential (EPSP) amplitude and spike onset latency. In addition, changes in the relationship between the EPSP and population spike amplitude indicated that granule cell excitability was enhanced during LTP and reduced during LTD. LTD occurred primarily after low-frequency stimulation (5 of 6 cases), and was always accompanied by striking changes in the EEG, most notably a biphasic slow potential. While the EEG changes were confined to the first 5 min after the tetanus, LTD lasted from 1 to 4 h. The nature of the EEG events is still unclear, it is suggested that they may represent a spreading depression-like episode. Finally, we found that LTP evoked by high-frequency stimulation was larger and generally reached peak magnitude faster than when it followed low-frequency stimulation. A possible mechanism and role for hippocampal LTD is proposed.     

Presynaptic inhibitory action of acetylcholine in area CA1 of the hippocampus

The effect of iontophoretically applied acetylcholin (ACh) was investigated in area CA1 of transverse hippocampal slices maintained in vitro. In synaptically activated regions of the dendritic field, ACh reduced the amplitude of the population spike recorded from the pyramidal layer. In dendritic regions which were not synaptically activated, ACh increased the amplitude of the population spike or it had no effect. The depressing effect of ACh was abolished in denervated dendritic regions. The intracellularly recorded excitatory postsynaptic potential (EPSP) decreased in amplitude when ACh was applied at the synaptic site. The resting membrane potential, the time course of the EPSP, and the membrane resistance were unaffected. ACh increased the excitability of afferent fibers and this was independent of synaptic transmission. We conclude that ACh in addition to its postsynaptic effects has a presynaptic site of action.     

Kindling with stimulation of the dentate gyrus. II. Effects on evoked field potentials

Once daily for 60 days, male hooded rats received unilateral high-frequency stimulation in the hilus of the dentate gyrus (DG), at an intensity sufficient to evoke afterdischarge (AD). Every 2nd day, evoked potentials were recorded from the hilus following stimulation of the PP with single 0.1 ms pulses at 6 current intensities. Changes in synaptic excitability of the dentate granule cells were monitored by measuring the amplitudes of the population spikes; changes in the strength of excitatory synaptic transmission were monitored by measuring the slopes of the excitatory postsynaptic potentials (EPSPs). Control rats, which were not given kindling stimulation, were tested for changes in synaptic transmission and excitability in the same way, at comparable times. In general, hilar stimulation resulted in a large decrease in population spike amplitudes to below baseline and control levels, accompanied by a paradoxical potentiation of EPSPs. Population spike amplitudes decreased more in rats that developed generalized stage-5 seizures (Generalized group) than in rats that did not progress beyond partial seizures despite 60 days of stimulation (Partial group). Conversely, EPSP slopes increased more in the Partial group than in the Generalized group. These results suggest that kindling stimulation may potentiate responsiveness of the directly activated dentate granule cells to inputs from the PP, but at the same time suppress the output of the granule cells resulting from this input. Furthermore, the results indicate that kindling is more closely allied to the suppression of output than to the potentiation of responsiveness to input.     

Differential effects of mu- and delta-receptor selective opioid agonists on feedforward and feedback GABAergic inhibition in hippocampal brain slices.

Previous studies have suggested that opioid receptor activation in the hippocampus increases pyramidal neuron excitability by reducing GABAergic inhibition. This hypothesis has received support with regard to mu-receptor agonists but has not been adequately tested with selective delta-receptor agonists. In the present investigation we compared the effects of the selective mu-opioid receptor agonist [Tyr-(D-Ala)-Gly-(N-Me-Phe)-Gly-ol]-enkephalin (DAGO) and the delta-receptor agonist [D-Pen2,D-Pen5]-enkephalin (DPDPE) to those of bicuculline methiodide (BMI) on extracellularly recorded feedforward (FFW) and recurrent (feedback; FB) inhibition. It was discovered that the control population spike response, evoked by Schaffer collateral/commissural axon stimulation, increased in response to DAGO, DPDPE, and BMI, while the secondary or test response increased only in the presence of DAGO and BMI. The resulting hypothesis that delta-opioid receptor activation facilitates synaptically evoked responses independently of a reduction of inhibition was investigated by examining the effect of DPDPE on the field EPSP response recorded in stratum radiatum of CA1, or postsynaptically on a burst response activated through antidromic stimulation of pyramidal neurons in low calcium medium. delta-Opioid receptor activation had no effect on either the field EPSP response or the burst response, suggesting that neither synaptic transmission nor postsynaptic excitability were augmented. Finally, the possibility that DPDPE acts to enhance pyramidal cell excitability independently of GABAergic transmission was further investigated by examining responses to both mu- and delta-opioid agonists following treatment with BMI (30 microM). Responses to DPDPE and DAGO were completely blocked by this treatment, supporting the involvement of a GABAergic circuit in the actions of these enkephalins. These results suggest that the delta-opioid receptor agonist DPDPE may mediate a reduction in GABAergic inhibition which is not detectable using paired stimulation techniques designed to examine FFW and FB inhibition in the hippocampal slice.     

Effects of prenatal protein malnutrition on kindling-induced alterations in dentate granule cell excitability. I. Synaptic transmission measures.

The effects of prenatal protein malnutrition upon the efficacy of excitatory synaptic transmission at the level of the perforant path/dentate granule cell synapse were examined during development of perforant path kindling in chronically implanted adults rats. Rats born to dams fed a low protein (6% casein) or control protein (25% casein) diet were fostered to lactating dams fed the 25% casein diet 24 h after birth and were maintained on this diet throughout life following weaning. Beginning at 90-120 days of age, animals received daily kindling stimulations applied to the perforant path. Extracellular field potentials recorded from the granule cell layer of the dentate gyrus in response to single-pulse stimulation of the perforant path were analyzed to determine the effects of prenatal protein malnutrition on the efficacy of synaptic transmission during the kindling process. Measures used for these analyses included the EPSP slope, an indicator of the level of synaptic drive, the population spike amplitude which is a measure of postsynaptic activation and cellular firing, and the ratio of the population spike amplitude relative to the corresponding EPSP slope value, which was used to evaluate the overall efficacy of synaptic transmission. animals of the 6%/25% diet group were found to have significantly lower afterdischarge thresholds, yet required significantly more daily kindling stimulations to develop generalized motor convulsions (stage 5 seizure) than control animals. Examination of dentate field potentials obtained prior to kindling revealed no significant between group differences in measures of EPSP slope or population spike amplitude. Statistically significant increases in measures of both the population EPSP slope and population spike amplitude were observed in both diet groups 24 h after the first kindled afterdischarge. The degree of increase in both of these measures was significantly greater in animals of the 6%/25% group. Evaluation of input/output measures obtained during kindling revealed a steady increase in the population EPSP slope for both diet groups with animals of the 6%/25% group showing significantly greater levels of enhancement in this measure than controls. Enhancement of population spike amplitudes reached maximal values in animals of the 25%/25% group within the first few kindling stimulations and these levels remained unchanged until the first stage 5 seizure. In contrast, animals of the 6%/25% group showed a continuous increase in the population spike amplitude measure during the entire kindling process. Appearance of the first generalized motor convulsion (stage 5 seizure) resulted in a decrease in population spike amplitudes in both diet groups, with animals of the 6%/25% group showing a significantly greater decrease in this measure than controls.(ABSTRACT TRUNCATED AT 400 WORDS)     

Analysis of the habituation-like changes in transmission in the temporodentate pathway of the rat

Habituation-like decrements in extracellular measures of synaptic activation (population EPSP) and cell discharge (population spike) were analyzed in the dentate gyrus of the rat following repetitive low-frequency stimulation of the medial and lateral entorhinal cortex. Stimulation of either subdivision of the entorhinal projection system resulted in comparable habituation-like response decrements with similar stimulation regimens. However, habituating stimulation of one subdivision did not result in decreased responsiveness to stimulation of the other. Repetitive low-frequency stimulation or even a single pulse delivered to either subdivision did, however, result in a potentiation of granule cell discharge in response to stimulation of the other subdivision (a form of heterosynaptic potentiation). This heterosynaptic potentiation of granule cell discharge was not accompanied by any increase in the extracellular EPSP. Comparisons of the relationship between the population EPSP and population spike before and during habituating stimulation revealed changes in cell discharge in response to the habituating stimulus which could not be accounted for by changes in synaptic activation alone. The results suggest that repetitive activation of the temporodentate pathway alters granule cell output as a result of two processes, a habituation-like decrement in synaptic activation, and a potentiation of granule cell discharge as a consequence of prior activation.     

Patterns of dentate granule cell responses to perforant path stimulation in epileptic mice with granule cell dispersion

In adult mice, intrahippocampal administration of kainic acid induces a structural modification of the granule cell layer reminiscent of granule cell dispersion (GCD) seen in humans with temporal lobe epilepsy. We tested that GCD might be involved in the patterns of granule cell responses to perforant path stimulation by recording field potentials in vivo after kainic acid-induced status epilepticus until the phase of chronic seizure activity in presence of GCD or after its alteration by K252a co-treatment, an inhibitor of tyrosine kinase activities. Stimulation triggered bursts of multiple population spikes, the number of which progressively increased with time whereas their amplitude decreased in parallel with the progressive decrease in granule cell density. The population spike threshold was reached for a lower excitatory synaptic drive than in controls, as assessed by the initial slope of the field excitatory post-synaptic potential. This indicates that, for identical synaptic responses, granule cells were closer to the firing threshold. Fast inhibition, assessed by paired pulse stimulation, was compromised immediately after the initial status epilepticus, consistent with the rapid loss of most hilar cells. Neither the epileptic course nor the epileptiform responses of the granule cells were modified and manipulation by alteration following GCD manipulation while granule cell neuropeptide-Y immunostaining was substantially decreased. In this mouse model of TLE, granule cells display a progressive increase in epileptiform responses to afferent input until the occurrence of spontaneous seizures. The population spike amplitude decreases in parallel with GCD while the granule cell excitability is enhanced. Consequently, data from field potentials in epilepsy experiments should be interpreted with care, taking into account the possible variations in the neuronal density in the recorded area.