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PubMedDate not supplied

Comparison of progabide with other antiepileptic and GABAergic drugs.

The effect of the experimental antiepileptic gamma-aminobutyric acid (GABA) agonist drug progabide, [alpha-(chloro-4-phenyl)fluor-5-hydroxy-2-benzilideneamino]-4-buty ramide, on the trigeminal complex of cats was compared with the effect of established antiepileptic drugs and with the effect of various GABA agonists and antagonists. Intravenous administration of 10-40 mg/kg progabide depressed excitatory transmission and descending periventricular inhibition, similar to carbamazepine and phenytoin. However, progabide depressed, rather than facilitated, segmental inhibition. The serum levels of progabide were comparable with those in patients receiving long-term treatment with progabide. The GABA antagonist bicuculline had the opposite effect of progabide on our experimental model, but the other GABA agonists THIP (4,5,6,7-tetrahydroisoxazolo-5,4-C-pyridine-3-ol) and muscimol did not have the same effects as progabide. THIP had no effect on excitatory transmission, periventricular inhibition, or segmental inhibition, whereas muscimol facilitated periventricular inhibition and sometimes segmental inhibition and had no effect on excitatory transmission. Our experiments thus indicate that progabide, but not THIP or muscimol, should have antiepileptic properties, in agreement with the clinical experiences that have been reported. The reason for the differential effect of these three GABA agonists remains to be elucidated.

Animals↗

PubMed1991

Participation of postsynaptic PKC in cerebellar long-term depression in culture.

Long-term depression (LTD) in the intact cerebellum is a decrease in the efficacy of the parallel fiber-Purkinje neuron synapse induced by coactivation of climbing fiber and parallel fiber inputs. In cultured Purkinje neurons, a similar depression can be induced by iontophoretic glutamate pulses and Purkinje neuron depolarization. This form of LTD is expressed as a depression of alpha-amino-3-hydroxy-5-methyl-4- isoxazole-propionic acid (AMPA)-mediated current, and its induction is dependent on activation of metabotropic quisqualate receptors. The effect of inhibitors of protein kinase C (PKC) on LTD induction was studied. Inhibitors of PKC blocked LTD induction, while phorbol-12,13-diacetate (PDA), a PKC activator, mimicked LTD. These results suggest that PKC activation is necessary for the induction of cerebellar LTD.

Animals↗

PubMed1983

Long-term potentiation in the hippocampus.

Long-term potentiation of field and single neuronal responses recorded in various hippocampal fields is described on the basis of author's and literary data. Most of intrahippocampal and extrinsic connections in both in vivo and in vitro hippocampal preparations show this phenomenon after one or several conditioning trains of comparatively short duration (20 s or less) at various frequencies (from 10 to 400 Hz). Properties of hippocampal potentiation are described. The properties include long term persistence (hours and days) of the potentiated response, its low frequency depression, self-restoration after the depression, specificity of the potentiation for the tetanized pathway, necessity of activation of a sufficient number of neuronal elements ('cooperativity') to produce the potentiation, possible involvement of 'reinforcing' brain structures during conditioning tetanization. These properties are distinct from those of 'usual' short-term post-tetanic potentiation and lead to the suggestion that the neuronal mechanisms underlying long-term post-tetanic are similar to those underlying memory and behavioral-conditioned reflex. Neurophysiological mechanisms of long-term potentiation are discussed. The main mechanism consists in an increase in efficacy of excitatory synapses as shown by various methods including intracellular recording and quantal analysis. The latter favours presynaptic localization of changes of synaptic efficacy showing increase in the number of transmitter quanta released per presynaptic impulse. However, changes in the number of subsynaptic receptors or localized changes in dendritic postsynaptic membrane are not excluded. Biochemical studies indicate the increase in transmitter release and calcium-dependent phosphorylation of pyruvate dehydrogenase after tetanization. Instances of persistent response facilitations at other levels of the vertebrate central nervous system (especially at neocortical level) are considered and compared with hippocampal long-term potentiation. It is suggested that modifiable excitatory synapses necessary for learning have been identified in studies of long-term potentiation. These synapses are presumably modified as a result of close sequential activation of the following three structures: excitatory presynaptic fibers, the postsynaptic neuron and a 'reinforcing' brain system.

Afferent Pathways↗

PubMed1991

Development of natural products as drugs acting on central nervous system.

We have recently studied several natural product constituents which have effects on the CNS. (1) Tetrahydropalmatine (THP) and its analogues were isolated from Corydalis ambigua and various species of Stephania. (+)-THP and (-)-THP possess not only analgesic activity, but also exert sedative-tranquilizing and hypnotic actions. Results of receptor binding assay and their pre- and post-synaptic effects on dopaminergic system indicate that (-)-THP and (-)-stepholidine are dopamine receptor antagonists while (+)-THP is a selective dopamine depletor. (2) 3-Acetylaconitine (AAC) is an alkaloid isolated from Aconitum flavum. The relative potency of analgesic action of AAC was 5.1-35.6 and 1250-3912 times that of morphine and aspirin, respectively. The analgesic effect of AAC was not antagonized by naloxone, but was eliminated by reserpine. In monkeys, after AAC was injected for 92 days, no abstinence syndrome was seen after sudden AAC withdrawal or when challenged with nalorphine. (3) Huperzine A (Hup-A) is an alkaloid isolated from Huperzia serrata which was found to be a selective ChE inhibitor and could improve learning and retrieval processes. Preliminary clinical studies showed that Hup-A improve short- and long-term memory in patients of cerebral arteriosclerosis with memory impairment. (4) Ranamargarin is a new tetradecapeptide isolated from the skin of the Chinese frog Rana margaratae. This peptide may mainly act on NK-1 receptor.

Amino Acid Sequence↗

PubMed1988

Frequency-dependent N-methyl-D-aspartate receptor-mediated synaptic transmission in rat hippocampus.

1. The effects of the N-methyl-D-aspartate (NMDA) antagonist, D-2-amino-5-phosphonovalerate (APV) were examined on synaptic responses evoked by high-frequency stimulation of the Schaffer collateral-commissural pathway, in the presence of Mg2+ (1 or 2 mM) and functional synaptic inhibition. 2. The synaptic response evoked by 100 Hz stimulation comprised fast excitatory postsynaptic potentials (EPSPs) evoked by each shock and a slow depolarization. APV reduced the size of the depolarization without depressing the fast EPSPs. 3. The mean (+/- 1 S.E.) amplitude of the APV-sensitive component (3.0 +/- 0.3 mV), evoked by 100 Hz stimulation at membrane potentials near rest, was invariably smaller than the first fast EPSP (9.8 +/- 0.7 mV). Both of these synaptic components had similar thresholds and increased in amplitude as the stimulus intensity was raised. There was a positive correlation between the amplitude of the two components (r = 0.57, P less than 0.01). 4. The amplitude of the APV-sensitive component was positively correlated (r = 0.97, P less than 0.05) with the frequency of stimulation during the trains (between 10 and 100 Hz). The threshold frequency for evoking an APV-sensitive component was approximately 10 Hz. 5. In contrast to the fast EPSPs the amplitude of the APV-sensitive component increased with depolarization, and decreased with hyperpolarization, of a neurone from its resting membrane potential. The component was no longer present in some cells which had been hyperpolarized sufficiently. 6. It is suggested that during high-frequency stimulation a neurone may become depolarized for a sufficient time to reduce the Mg2+ block of NMDA channels. This enables the NMDA receptor system to contribute transiently to the synaptic response, despite the inhibitory synaptic mechanisms which prevent its activation during single-shock stimulation. The characteristics of the NMDA receptor-mediated synaptic response may explain properties relating to the induction of long-term potentiation (LTP).

2-Amino-5-phosphonovalerate↗

PubMed1990

Differential effect of gepirone on presynaptic and postsynaptic serotonin receptors: single-cell recording studies.

The sustained administration of the serotonin (5-hydroxytryptamine1A, 5-HT1A) agonist gepirone (15 mg/kg/day subcutaneously) in the rat produced an initial decrease of the firing activity of dorsal raphe 5-HT neurons, which was followed by a progressive recovery to normal after 14 days of treatment. At this point, the somatodendritic 5-HT1A autoreceptor had desensitized, as indicated by the reduced effectiveness of intravenous lysergic acid diethylamide (LSD) and of microiontophoretic applications of 5-HT, LSD, 8-hydroxy-2-(N,N-propylamino) tetralin (8-OH-DPAT), and gepirone, but not of gamma-aminobutyric acid in depressing the firing activity of 5-HT neurons. In contrast, the responsiveness of postsynaptic dorsal hippocampus pyramidal neurons to 5-HT, 8-OH-DPAT, and gepirone was not altered by the 14-day gepirone treatment. In an attempt to unravel the differential effect of sustained gepirone administration on presynaptic and postsynaptic 5-HT1A receptors, the properties of gepirone at these two receptors were assessed. The concurrent microiontophoretic application of gepirone readily blocked the effect of 5-HT on dorsal hippocampus pyramidal neurons, but not on dorsal raphe 5-HT neurons, thus indicating that gepirone is a partial agonist at postsynaptic 5-HT1A receptors and a full agonist at somatodendritic 5-HT1A receptors. It is proposed that gepirone, being a partial agonist at postsynaptic 5-HT1A receptors, fails to desensitize them; whereas, because of its full agonistic activity at the somatodendritic 5-HT1A receptor, it desensitizes this autoreceptor with long-term administration.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1992

Use-dependent fade and slow recovery of long-term potentiation in superior cervical ganglion of the cat.

1. In anesthetized cats under partial block of nicotinic ganglionic transmission by hexamethonium and in which the cervical sympathetic trunk (CST) was split into two bundles of approximately equal size, a 40-Hz 5-s conditioning stimulus train to one bundle produced prolonged potentiation of the postganglionic compound action potential evoked by a test stimulus to the same or to the other bundle [homosynaptic and heterosynaptic, respectively, long-term potentiation (LTP)]. The LTP was detected also by recording the nictitating membrane (NM) contraction in response to a test preganglionic train. 2. The homosynaptic or heterosynaptic LTP produced by applying the conditioning 40-Hz 5-s train to one bundle was markedly depressed in amplitude and duration after stimulation of that bundle at 40 Hz for 20 min, whereas the homosynaptic or heterosynaptic LTP produced by applying the conditioning 40-Hz 5-s train to the other bundle was unchanged. The latter evidence suggests that all superior cervical ganglion (SCG) synapses can still express LTP during the depression that follows the 40-Hz 20-min train. 3. In 4 h there was no appreciable recovery of LTP from the depression produced by a 40-Hz 20-min train (n = 5). However, after 3 days (n = 3) and 5 days (n = 3), LTP recovered to 53 and 90% of control, respectively. 4. When colchicine was applied to the CST bilaterally, at a concentration sufficient to block fast axonal transport, and one CST only was stimulated for 20 min at 40 Hz, the LTP recorded 4 days later was significantly smaller on the stimulated than on the contralateral, control, side.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1991

Long-term potentiation of nicotinic transmission by a heterosynaptic mechanism in the stellate ganglion of the cat.

1. In the anesthetized, scopolamine-treated cat, the compound action potential (CAP) evoked by a single supramaximal shock to the third thoracic white ramus (T3WR) was recorded in the inferior cardiac nerve (ICN). The CAP was depressed in a dose-dependent manner by the intravenous administration of the nicotinic antagonist hexamethonium (C6). 2. During steady intravenous infusion of C6, which reduced the amplitude of the CAP by 80-90%, a short train of stimuli (few seconds, 10-40 Hz) to the sympathetic trunk just below T4WR potentiated the CAP for periods of tens of minutes to 1-2 h (heterosynaptic long-term potentiation, LTP). An LTP of similar time course was obtained when both train and single shock were applied to T3WR (homosynaptic LTP). Magnitude and duration of the heterosynaptic LTP were dependent on number, frequency, and intensity of the stimuli. No LTP was produced by a train to the ICN. Heterosynaptic LTP was also observed in the absence of C6. Because of the limited subliminal fringe of the test input under this condition, the LTP was of small magnitude. Heterosynaptic LTP also of the heart rate (HR) response to a test stimulus was observed after a conditioning train. 3. The conditioning train produced a displacement to the right of the dose-response curve for C6. The intravenous dose of C6 required for 50% attenuation of the test CAP increased from 0.84 +/- 0.15 (SE) mg/kg pretrain to 2.56 +/- 0.46 mg/kg posttrain (n = 5, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1990

Striatal preprotachykinin and preproenkephalin mRNA levels and the levels of nigral substance P and pallidal Met5-enkephalin depend on corticostriatal axons that use the excitatory amino acid neurotransmitters aspartate and glutamate: quantitative radioimmunocytochemical and in situ hybridization evidence.

Because excitatory amino acid (EAA) neurotransmission has been implicated in long-term postsynaptic events, we conducted an initial study to determine whether or not the EAA-utilizing corticostriatal projection might influence peptide biosynthesis in neurons of the rat's basal ganglia. The content of EAAs in the caudatoputamen was reduced by frontal cortical ablation or by chronic intracerebroventricular infusion of methionine sulfoximine (MS). At 7 days following cortical ablation striatal Asp and Glu were reduced by 15% and 24%, respectively, while MS infusion (24 micrograms/day) for 7 days reduced synaptosomal levels of Asp by 61% and Glu by 48%. With either treatment, quantitative radioimmunocytochemistry revealed that substance P (SP) in the substantia nigra was increased by approximately 38%, while Met5-enkephalin (ME) in the globus pallidus was not changed. In situ hybridization with oligonucleotide probes revealed changes in the rostral striatum of preprotachykinin (PPT) and preproenkephalin (PPE) mRNA levels: cortical ablation reduced PPT mRNA by 17% and PPE mRNA by 20% dorsally, while it increased PPE mRNA (but not PPT mRNA) by 23% ventrally. Likewise, the infusion of MS decreased PPT (32%) and PPE mRNA (28%) dorsally, and increased PPE mRNA (50%) ventrally. In addition to the 7 day time point, the same measurements of EAAs, peptides and mRNAs were made at 14, 21 and 28 days after cortical excisions. At 14 days, the level of striatal Asp had returned to control value, but Glu remained depressed by 21%; nigral SP remained increased by 24%, and pallidal ME decreased by 15%. PPT and PPE mRNA remained depressed dorsally by 15% and 25%, respectively, while the increase in PPE mRNA noted ventrally at 7 days had returned to control values by 14 days. With the exception of Glu, which remained depressed by 18% at 21 and 28 days, all other values had returned to control levels by 21 days. The results indicate that a large reduction in EAA neurotransmission can influence differentially the steady-state levels of neuropeptides in striatal neurons and this change is brought about, at least in part, by an alteration in gene transcription.

Animals↗

PubMed1984

Influences of sinusoidal electric fields on excitability in the rat hippocampal slice.

The influence of extracellular sinusoidal electric fields on the amplitude of population spikes evoked by single test pulses in excitatory pathways to CA1 pyramidal neurons was studied in rat hippocampal slices. The fields in the tissue were of the order of EEG gradients. Stimulation at 5 Hz, a frequency representative of hippocampal theta activity, was compared with 60 Hz, which is often used in kindling procedures. Brief stimulation (5-30 s) with both 5 and 60 Hz fields (20-70 mV/cmp-p in the perfusing solution) often produced a long-term increase (longer than 10 min) of the population spike. Fields at 60 Hz, but not at 5 Hz, also induced short-term depression (1-6 min) or transient post-field excitation (15-30 s). Prolonged stimulation (3 min) emphasized this frequency dependent response: fields at 5 Hz induced long-lasting potentiation while fields at 60 Hz always resulted in progressive depression persisting for a few minutes after the end of stimulation. These effects appeared as a global response of CA1 neurons. Antidromic responses studied during blockade of synaptic transmission (0.2 mM Ca2+, 4 mM Mg2+) were depressed during and following 3 min field stimulation at either frequency, which could reflect failing calcium mechanisms in the tissue. The field influence on the potential evoked by synaptic or antidromic stimulation was independent of the phase of the sine wave at which the test pulse was delivered, arguing against a direct polarization of the cell membrane by the fields. The experimental evidence suggests a functional role for EEG-like fields in hippocampal excitability.

Animals↗

PubMed1985

Functional plasticity in two afferent systems of the granule cells in the rat dentate area: frequency-related changes, long-term potentiation and heterosynaptic depression.

Monosynaptic evoked field potentials (MEFP) were recorded in the dentate gyrus of male Wistar rats upon stimulation of either the perforant path or the commissural system. While the perforant path potential exhibited in acute experiments a clear reversal point of the field excitatory postsynaptic potential (EPSP) and population spike when protruding the registration electrode from the hippocampal fissura to the hilus of the dentate gyrus, the simultaneously registered commissural potential elicited by stimulation of the contralateral hilus showed no reversal of the negative monophasic wave but merely an amplitude maximum 40 microns above the reversal point of the perforant path potential. Frequency-related changes of the MEFPs during short tetanic stimulation with 15 Hz both in acute and chronic experiments, revealed differences in the properties of the input systems in that the commissural potential exhibited a clear frequency potentiation whereas the perforant path potential showed frequency depression. Pronounced long-term potentiation of the perforant path potential induced by 4 trains of tetanizing stimuli and lasting up to 72 h was accompanied by a long-term heterosynaptic depression of the commissural potential for up to 7 days after tetanization. Both the different frequency-related changes of the inputs and the extremely long duration of the heterosynaptic depression are discussed with respect to their proposed functions in the mechanisms of functional plasticity.

Animals↗

PubMed1988

Activation of protein kinase C induces a long-term depression of glutamate sensitivity of cerebellar Purkinje cells. An in vitro study.

In immature rat cerebellar slices in vitro, a long term depression (LTD) of the responses of Purkinje cells (PCs) to L-glutamate (Glu) was achieved in 30% of the recorded cells by simultaneous stimulation of the neurones by Glu and by climbing fibres (CFs). This effect was not observed for L-aspartate (Asp)-induced responses. Similarly, selective LTD of Glu-induced responses was obtained in 22% of the cells by pairing Glu applications with direct stimulation of the cells which elicited calcium spikes in these neurones. Finally, bath application of phorbol esters also induced a selective LTD of Glu-induced responses in all cells tested. These results suggest that protein kinase C is involved in cerebellar synaptic plasticity.

Animals↗

PubMed1990

Long-term potentiation in rat hippocampus is inhibited by low concentrations of ethanol.

Acute ethanol ingestion impairs memory in humans at concentrations associated with mild intoxication. A possible neurophysiological correlate of this effect is the suppression by ethanol of long-tem potentiation (LTP), a persistent increase in synaptic efficiency which has been proposed as a substrate for memory. However, in previous studies ethanol has been shown to impair LTP only at very high concentrations, near the lethal level in humans. We now report that ethanol can significantly reduce LTP in rat hippocampus at concentrations as low as 5 mM, a level attainable following ingestion of a single alcoholic drink. We also demonstrate that the potency of ethanol in depressing LTP correlates well with its potency in inhibiting the response to N-methyl-D-aspartate, an agonist at the glutamate receptors implicated in LTP induction. The influence of low ethanol concentrations on LTP may contribute to the memory impairment associated with its use in humans.

Animals↗

PubMed1992

Long-term potentiation induced by patterned stimulation of the commissural pathway to hippocampal CA1 region in freely moving rats.

In urethane-anesthetized rats, stimulation of the contralateral hippocampal CA1 region resulted in activation of the homotopic CA1 region. Current-source-density analysis revealed that both basal and apical dendrites were activated. However, alveolar and stratum oriens stimulation in CA1 gave about equal peak excitation of the basal and apical dendrites while CA1 stratum radiatum/moleculare and CA3c stimulation gave stronger apical than basal dendritic excitation. In chronically implanted and freely moving rats, tetanic patterned stimulation of the contralateral CA1, irrespective of depth, resulted in a robust long-term potentiation of the ipsilateral CA1 basal dendritic synapse. The population basal dendritic excitatory postsynaptic potential was initially potentiated to greater than 200% of the baseline and decayed with a 3 h time constant; it lasted at least two days. Patterned stimulation of the commissural inputs at 2 x threshold stimulus intensity seldom potentiated the apical dendritic synapse in CA1; rather, long-term depression was sometimes observed. After tetanic stimulations at 3 x threshold, a small potentiation of the apical dendritic excitation was seen in about half of the experiments. The average apical dendritic potentiation peaked at about 25% and persisted to at least one day. This study provides original evidence that the properties of long-term potentiation are different at the commissural basal dendritic and apical dendritic synapses in CA1 of the behaving rat. Basal dendritic potentiation is low-threshold, high-amplitude and decayed rapidly in the first 3 h. Apical dendritic potentiation is high-threshold, low-amplitude and not rapidly decaying. A long-lasting enhancement of synaptic transmission has been postulated as a physiological correlate of memory. This paper reports properties of this synaptic enhancement for two different types of synapses on the same cells in the behaving animal. The basal dendritic synapse on hippocampal pyramidal cells readily increased their efficacy, up to at least two days, after a brief, patterned stimulation. In the same preparation, it was difficult to obtain a long-lasting increase in the apical dendritic excitation, in contrast to studies on isolated hippocampal slices in vitro.

Animals↗

PubMed1989

Effect of volatile anesthetics on synaptic transmission in the rat hippocampus.

The synaptic effects of halothane, isoflurane, and enflurane were examined in the rat hippocampus in vivo and compared with the effects of ketamine and urethane. Actions of the agents on excitatory amino acid-mediated neurotransmission were studied by observing evoked responses and long-term potentiation in the stratum pyramidale of CA1 with stimulation of the contralateral CA3 region. Long-term potentiation is a long-lasting increase in synaptic efficacy, which follows a brief stimulus train. It has been shown to be established through activation of the NMDA subclass of excitatory amino acid receptors and is thought to be involved in memory processing. Volatile anesthetics had no effect on evoked excitatory responses or on long-term potentiation. Actions of the anesthetics on inhibitory processes in the hippocampus were studied by pairing stimuli at a range of interpulse intervals. The first stimulus activated inhibitory processes that caused the response to the second stimulus to be smaller than the initial response, a phenomenon termed paired pulse depression. Paired pulse depression was significantly prolonged by the volatile anesthetics compared with that under urethane or ketamine. These results indicate that the mechanism of action of the volatile anesthetics at the hippocampal CA1 synapse does not involve amino acid-mediated excitation but does involve enhancement of inhibition.

Animals↗

PubMed1990

Hippocampal synaptic plasticity and NMDA receptors: a role in information storage?

There has recently been renewed interest in the idea that alterations in synaptic efficacy may be the neural basis of information storage. Particular attention has been focused upon long-term potentiation (LTP), a long-lasting, but experimentally induced synaptic change whose physiological properties point to it being a candidate memory mechanism. However, considerations of storage capacity and the possibility of concomitant activity-dependent synaptic depression make it unlikely that individual learning experiences will give rise to gross changes in field potentials similar to those that occur in LTP, even if learning and LTP utilize common neural mechanisms. One way of investigating the functional significance of LTP is to use selective antagonists of those excitatory amino acid receptors whose activation is essential for its induction. This paper discusses various design requirements for such experiments and reviews work indicating that the N-methyl-D-aspartate receptor antagonist AP5 causes a behaviourally selective learning impairment having certain common features to the behavioural profile seen after hippocampal lesions. Two new studies are described whose results show that AP5 has no effect upon the retrieval of previously established memories, and that the dose-response profile of the impairment of spatial learning occurs across a range of extracellular concentrations in hippocampus for which receptor selectivity exists. These experiments show that activation of NMDA receptors is essential for certain kinds of learning.

Animals↗

PubMed1985

Long-term changes in hippocampal physiology and learning ability of rats after intrahippocampal tetanus toxin.

A chronic epileptic syndrome can be induced by injecting minute doses of tetanus toxin into rat hippocampi. This causes intermittent epileptic fits over a period of 2-4 weeks, after which the fits cease, and the electroencephalogram (e.e.g.) appears to return to normal over the following 2-3 weeks. However, once they have recovered from the seizures, the rats exhibit a remarkably persistent impairment of learning and memory, which is the subject of the present study. Learning ability was assessed using a radial arm maze task, in which the rats had to visit each of eight arms for a food reward. The toxin-injected rats learnt this task more slowly than control-injected. Evoked potentials from the CA3 pyramidal cells were recorded in terminal experiments under halothane anaesthesia. Long term potentiation of the post-synaptic response to the commissural pathway from the contralateral hippocampus appeared to be unaffected by the previous toxin treatment, at least over periods of up to 5 h. The toxin-injected group differed from the control in having consistently smaller post-synaptic population spikes in their evoked responses, so that stimuli were less effective in exciting the post-synaptic neurones. This applied both to the contralateral commissural input, and to the ipsilateral mossy fibre input. No differences were found between the toxin and control groups in the size of the antidromic population spike in the commissural response, or in the population excitatory post-synaptic potential (e.p.s.p.) for either input. Thus the depressed output from CA3 pyramidal cells cannot be explained either by a loss of these neurones (confirming earlier neuropathological observations), or by a loss of excitatory afferents. While its precise cause remains unknown, the depressed output from the CA3 region was statistically correlated with the learning impairment, and we believe provides a reasonable explanation of this behavioural deficit.

Action Potentials↗

PubMed1988

Postsynaptic control of the induction of long-term changes in efficacy of transmission at neocortical synapses in slices of rat brain.

1. Long-term potentiation (LTP) is an enduring, activity-induced increase in the efficacy of synaptic transmission, which has been considered as a possible neural substrate for learning. Recent experiments have shown that LTP can be induced in hippocampal CA1 neurons when a presynaptic volley is paired repetitively with depolarization of the postsynaptic cell, brought about with intracellularly applied depolarizing current pulses (20, 33). We have repeated these experiments in neocortical neurons, in transverse slices of rat sensorimotor cortex in vitro. 2. Stable intracellular recordings were obtained from 28 neurons (mean resting potential -78 mV, mean spike amplitude 95 mV, mean input resistance 41 M omega) mostly in layers V and VI. Two different afferent pathways were stimulated alternately at 0.2 Hz to evoke subthreshold composite excitatory postsynaptic potentials (EPSPs). One micromolar bicuculline methiodide was added to the bathing medium in most experiments. 3. Repetitive pairing of one afferent volley with a coincident intracellular depolarizing current pulse (100-200 ms long) of a magnitude sufficient to make the neuron fire 6 to 13 action potentials/pulse, gave rise after 30-50 pairings in 4 neurons to a significant enduring increase in the amplitude of the paired EPSP. The increase persisted without decrement for as long as the recording continued (range 15-50 min after the pairing ended) but the amplitude of the unpaired EPSP was unchanged. During the LTP, the membrane potential and the apparent input resistance of the postsynaptic neurons were also unchanged. 4. In two cells a significant prolonged depression of the paired EPSP was induced while the unpaired EPSP was unaffected. Membrane potential and input resistance were not changed. In the remaining 22 cells neither the paired nor the unpaired EPSP was altered. 5. Brief, tetanic stimulation was applied to one afferent pathway in 11 of the neurons in which postsynaptic stimulation had been ineffective. A variety of effects was produced (LTP, depression, or posttetanic potentiation). All the effects of tetanic stimulation were confined to the stimulated pathway. 6. We conclude that LTP can be produced in some neocortical neurons by pairing a presynaptic volley with postsynaptic depolarization, in an experimental paradigm that conforms to Hebb's (17) model of associative conditioning. Depression of the paired EPSP was produced in other cells with the same experimental design.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗