Heterosynaptic depression: a postsynaptic correlate of long-term potentiation.
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Afferent Pathways↗
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Results for “Long-Term Synaptic Depression”
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Cerebellar long-term potentiation under suppressed postsynaptic Ca2+ activity.
To study the roles of postsynaptic Ca2+ activity in cerebellar synaptic plasticity, we used a patch-recording technique in Purkinje cell dendrites. While the combination of parallel fibre stimulation and 8-bromo cyclic guanosine monophosphate (Br-cGMP) application produced long-term depression (LTD) of the parallel fibre/Purkinje cell transmission, the same stimuli evoked long-term potentiation (LTP) during postsynaptic injection of Ethyleneglycol-bis-(beta-amino-ethylether)-N, N, N', N'-tetraacetate (EGTA). Furthermore, in the presence of alpha-aminobutyric acid (GABA), parallel fibre stimulation plus Br-cGMP produced LTP of extracellular K+ increases following parallel fibre stimulation. These results suggest that postsynaptic Ca2+ activity in Purkinje cells is negatively correlated to the direction of plastic changes and that the Ca2+ changes and cGMP play distinct roles in cerebellar synaptic plasticity.
Animals↗
Long term changes in augmentation, potentiation, and depression of transmitter release as a function of repeated synaptic activity at the frog neuromuscular junction.
1. End-plate potentials (e.p.p.s) were recorded from frog neuromuscular junctions under conditions of low quantal content to study the long-term effects of repeated synaptic activity on transmitter release. 2. The nerve terminal was presented with 30-100 successive conditioning-testing trials applied once every 7-10 min over a 4-16 hr perod. Each conditioning-testing trial consisted of a 200-600 impulse conditioning train followed by a series of testing impulses. The magnitudes and time constants of decay of augmentation and potentiation following each successive conditioning train were determined by measuring the e.p.p. amplitudes resulting from the testing impulses. 3. The magnitude of augmentation immediately following the conditioning trains increased an average of 3-4 times (range 1-20) with sucessive trials. 4. As the magnitude of augmentation increased with successive trials the decay of augmentation deviated from a simple exponential, decaying faster immediately after the conditioning train. This faster decay led to a 20% decrease with successive trials in estimates of the time constant obtained from the first 10 or 20 sec of the decay of augmentation. The deviation of the decay of augmentation from a simple exponential could be accounted for if augmentation is related to the 4th power of some substance which decays with a simple exponential time course. Some alternative explantations for the non-exponential decay of augmentation are also discussed. 5. The magnitude of potentiation increased or decreased about 25% with successive trials. 6. The time constant characterizing the decay of potentiation inceased an average of 1-5 times (range 0-8-5 times) with successive trials. 7. The increase in the magnitude of augmentation with successive trials was accompanied by a similar increase in the magnitude of the e.p.p. amplitudes during the conditioning trains, suggesting that augmentation develops during the conditioning train. In some preparatons augmentation appeared to be the major factor acting to increase e.p.p. amplitudes during the conditioning train, having a greater effect than facilitation or potentiation. 8. If a sufficiently large number of successive trials were applied, a depression of e.p.p. amplitudes developed during the conditioning trains and estimates of the magnitude of potentiation following the depressed conditioning trains were reduced...
Animals↗
Altered Excitation-Inhibition Balance and mGluR1/5-Driven Plasticity in the Motor Cortical Surface in a Rat Model of Parkinson's Disease.
Parkinson's disease (PD) is characterized by progressive dopaminergic degeneration and maladaptive motor cortical plasticity. However, the cellular pathways underlying cortical surface activity in the primary motor cortex (M1) remain unclear, despite serving as a potential target for electrotherapy. We investigated the excitatory-inhibitory (E-I) balance and synaptic plasticity of superficial M1 circuits in a unilateral 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Using extracellular local field potential and whole-cell patch recordings from the contralateral and ipsilateral M1 hemispheres of hemi-parkinsonian rats, we observed a significantly elevated field excitatory postsynaptic potential (fEPSP) input-output function but unchanged intrinsic neuronal excitability in the M1 superficial layer. An altered relative contribution between alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and N-methyl-D-aspartate receptor (NMDAR)-mediated transmission was reflected by a significantly increased AMPA/NMDA ratio. Markedly reduced inhibitory synaptic tone was also evidenced by the decreased amplitude and frequency of spontaneous inhibitory postsynaptic currents (sIPSCs), supporting an E-I imbalance favoring excitation in PD. Furthermore, group I metabotropic glutamate receptor (mGluR1/5)-dependent long-term depression (LTD) was abolished in the ipsilateral PD hemisphere, whereas NMDAR-dependent LTD remained intact. In summary, dopamine depletion appears to enhance network excitation and disrupt mGluR1/5-mediated control of M1 surface circuitry. Our findings identify altered cortical surface mGluR-dependent plasticity in the hemi-parkinsonian model; however, the relationship between these electrophysiological alterations and individual motor outcomes remains to be determined.
Animals↗
Tardive dyskinesia and depressive illness.
Tardive dyskinesia has been regarded as a long-term complication of neuroleptic administration to patients with the diagnosis of schizophrenia. However, nine of the first fourteen patients evaluated for an investigation of tardive dyskinesia met diagnostic criteria for depression. Neuroleptics produce blockade of post-synaptic dopaminergic receptors. Tardive dyskinesia occurs when neuroleptics are discontinued, and is regarded as a manifestation of super-sensitive post-synaptic dopaminergic receptors. Tardive dyskinesia occurs when neuroleptics are discontinued, and is regarded as a manifestation of super-sensitive post-synaptic dopaminergic receptors. Chronically decreased neurotransmission in the synapse of a patient with depression may contribute to the development of a super-sensitive receptor and could explain the high proportion of patients with depression seen in this sample of patients with tardive dyskinesia.
Antidepressive Agents, Tricyclic↗
[Short and long term depression of neuromuscular transmission in crayfish].
Following single excitation of the abdominal giant motoneuron of crayfish, an important depression of neuro-muscular transmission is observed for about 15 mn. The time course of recovery is not modified even after low frequency (1/30 Hz) repetitive stimulation. Recovery curves obtained for different Mg++ concentration in physiological solutions show two phases of depression: short-term depression which is largely reduced in high Mg++ concentrations - thus probably depending on transmitter depletion in motoneuron terminals - long-term depression which is not modified by changing Mg++ concentration and seems to be independent of depletion.
Abdomen↗
Coactivation of metabotropic glutamate receptors and of voltage-gated calcium channels induces long-term depression in cerebellar Purkinje cells in vitro.
Using an in vitro slice preparation, we studied the effects, on parallel fiber (PF)-mediated EPSPs, of coactivation of metabotropic-glutamate receptors and of voltage-gated calcium (Ca) channels of Purkinje cells (PCs) by bath application of 50 microM trans-1-amino-cyclopentyl-1,3-dicarboxylate (trans-ACPD) and by direct depolarization of the cells, respectively. These effects were compared with changes in synaptic efficacy obtained when alpha-amino-3hydroxy-5-methylisoxalone-4-propionate (AMPA) receptors of PCs were also activated through stimulation of PFs during the pairing protocol, as well as when similar experiments were performed without trans-ACPD in the bath. In a control medium, pairing for 1 min of PF-mediated EPSPs evoked at 1 Hz with Ca spikes evoked by steady depolarization of PCs (n = 13) led to LTD of synaptic transmission in 9 cases whereas for the others EPSPs were not affected. No LTD occurred in 9 out of 10 other cells tested when PF stimulation was omitted during the 1 min period of Ca spike firing of PCs. Bath application of 50 microM trans-ACPD, in conjunction with the same pairing protocol as before (n = 8), led to a significantly larger LTD of PF-mediated EPSPs after washing out of this drug. Moreover, a clear-cut LTD of PF-mediated EPSPs was also observed in 5 of the 8 other cells, when PF stimulation was omitted during Ca spike firing in the presence of trans-ACPD.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Further evidence for a change in central alpha-adrenergic receptor sensitivity after withdrawal from long-term haloperidol treatment.
Phenoxybenzamine, FLA-63 and alpha-MT produced less locomotor depression in mice withdrawn for 4 days from a 21 day treatment with haloperidol than that produced in vehicle-treated animals. There were no differences between the two groups when challenged with yohimbine or phentolamine. The data support the hypothesis that central alpha-adrenergic receptors had become supersensitive and suggest that the sensitivity changes are restricted to post-synaptic receptors.
Animals↗
[Dopa and dopamine agonists in depression (author's transl)].
Following a summary of the functional organisation of the ascending dopamine systems, the pharmacology of the dopamine synaptic receptors is considered. The stress is placed upon the differences induced by dopamine agonists during short-term and long-term treatment. In this connection, recent ideas on the heterogeneous nature of the dopamine receptors, on their specificity and on their functional role will be discussed. The dopaminergic action of certain antidepressants will be studied by analysing the different types of activity: presynaptic release, direct pre- or post-synaptic agonism. The role of dopaminergic transmission in depression of mood is considered finally on the basis of clinico-biochemical correlations. Finally, dopaminergic activity is linked with the other possible changes in cerebral monoamines by drafting a table of the interactions between the neurotransmitters.
Animals↗
Low-frequency transcutaneous nerve stimulation in mild/moderate hypertension.
Low-frequency peripheral nerve stimulation may induce widespread cutaneous and muscular vasodilatation in animals and humans due to sympatho-inhibition. This response has in humans been shown to be associated with a lowering of the systemic vascular resistance and arterial pressure. In the present study the effectiveness of low-frequency (2 Hz) transcutaneous electrical nerve stimulation (TNS) has been examined in 46 patients, all 41-43 years of age, with a primary diagnosis of uncomplicated mild/moderate hypertension (90-115 mmHg diastolic pressure). The study was designed blind with matched controls in a TNS group and a placebo group. The blood pressure was measured objectively with an automatic monitor. In a short-term experiment TNS produced a significant lowering of systolic, mean arterial, and diastolic pressures amounting to 8 mmHg (P less than 0.01), 6 mmHg (P less than 0.01), and 4 mmHg (P less than 0.02), respectively. In a long-term study, after 2 weeks of daily stimulation, a similar depression was recorded with no stimulation on the day of examination. An eventual clinical use of the depressor effect of TNS demands further clinical research.
Adult↗
Heterosynaptic postactivation potentiation in hippocampal CA 3 neurons: long-term changes of the postsynaptic potentials.
CA 3 neurons were excited synaptically by stimulation in the dentate hilus and the stratum radiatum of CA 1 in guinea pig hippocampal slices. Following repetitive stimulation (10--20 c/s, 10 s) of either stimulation site, the amplitudes of orthodromic population spikes or the probability of unitary discharges increased. Changes of the intracellularly recorded potentials were either (a) increased EPSP amplitudes associated with decreased IPSP amplitudes, or (b) increased IPSP amplitudes. A cell showing enhanced IPSPs after repetitive activation could respond with increased EPSP amplitudes and decreased IPSP amplitudes upon further repetitive activation. The potentiation, which was always preceded by a 5--10 min depression, lasted up to 3 h. This potentiation was heterosynaptic, since the responses to the non-stimulated input also changed and since the inputs were found to excite the pyramidal cells through separate synapses in double shock experiments. The heterosynaptic mode of the potentiation as well as the changes of the IPSPs indicate that not only the excitatory pathway but also the inhibitory pathway must be considered in explaining postactivation potentiation in this hippocampal field.
Animals↗
Ketamine blocks the induction of LTP at the lateral entorhinal cortex-dentate gyrus synapses.
In many regions NMDA receptor activation is required for the synaptic induction of long-term potentiation (LTP). This role for NMDA receptors is controversial at the synapses formed between the cells of the lateral entorhinal cortex (LEC) and the dentate gyrus (DG). Using anesthetized rats, the present study shows that ketamine reversibly blocks the induction of LTP at the LEC-DG synapses, thus favoring a role for NMDA receptors in the induction of LTP there. Ketamine also reversibly blocks the induction of the small translaminar depression of the medial EC response or of the LEC response by conditioning the other system while the test system is inactive.
Animals↗
NMDA-dependent heterosynaptic long-term depression in the dentate gyrus of anaesthetized rats.
This report examines the inductive mechanisms involved in long-term heterosynaptic depression (LTD) in the dentate gyrus of anaesthetized rats. Associative and non-associative stimulus protocols were implemented, using the ipsilateral medial and lateral perforant path inputs to the dentate gyrus as the test pathways. In all experiments, the medial perforant path (MPP) received the conditioning stimuli which consisted of eight stimulus trains of 2 s duration, spaced 1 minute apart. Within each train the stimuli occurred as a burst of 5 pulses at 100 Hz, repeated at 200 ms intervals. The lateral perforant path (LPP) served as the test pathway in all of the initial experiments. In the associative condition, it received single pulses equally spaced between the medial path bursts. In the non-associative condition, no lateral path stimuli were given during the medial path trains. In both conditions, the application of the conditioning stimuli resulted in a long-term potentiation (LTP) of the medial path evoked responses (P less than 0.001), while the lateral path responses showed LTD (P less than 0.001). A two-way analyses of variance revealed there to be no difference between the two paradigms in the expression of LTP or LTD in naive pathways or in their ability to depress a potentiated pathway (P greater than 0.05) An occlusion test also showed there to be no further decreases in synaptic efficacy with the associative paradigm after the lateral path synapses were saturated with non-associative LTD.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
Induction of long-term potentiation in the basolateral amygdala does not depend on NMDA receptor activation.
Long-term potentiation (LTP) can be induced in the lateral and basolateral amygdala by stimulating synaptic afferents in the external capsule (EC). We examined the sensitivity of amygdaloid LTP to the NMDA receptor antagonist 2-amino-5-phosphonopentanoate (AP5), which is known to block LTP induction in the Schaffer collateral/CA1 synapses in the hippocampus. While relatively high concentrations (100 microM) of DL-AP5 were effective in preventing LTP induction in the lateral and basolateral amygdala in vitro, the same concentrations also significantly depressed synaptic responses to low-frequency stimulation. Furthermore, at 50 microM, a concentration sufficient to block both synaptic responses mediated by NMDA receptors and LTP induction in the hippocampus and neocortex, AP5 did not affect the probability of inducing LTP in the amygdala. Application of 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), which blocks non-NMDA excitatory amino acid receptors, reduced the monosynaptic response to EC stimulation by 85%. The remaining CNQX-insensitive response did not appear to be mediated by NMDA-type receptors, since it was not reduced by 50 or 100 microM AP5, and showed none of the voltage sensitivity characteristic of NMDA responses. These data suggest that while the induction of LTP in the amygdala produced by EC stimulation is blocked by high doses of AP5, plasticity at these synapses probably does not require activation of NMDA receptors.
2-Amino-5-phosphonovalerate↗
A role for protein kinase C in long term potentiation of nicotinic transmission in the superior cervical ganglion of the rat.
The superior cervical ganglion of rats was perfused with Ringer solution containing hexamethonium to produce a steady, partial, nicotinic block. The compound action potential (CAP) evoked by supramaximal single shock stimulation of the cervical sympathetic trunk (CST) was recorded from the internal carotid nerve. Bolus injection of the protein kinase C (PKC) activators 4 beta-phorbol-12,13-dibutyrate (PDBu) or 4 beta-phorbol-12,13-diacetate (PDAc) produced a marked, prolonged, dose-dependent potentiation of the CAP amplitude (e.g. 90% decay 2 h). A non-PKC activating phorbol ester (PE), 4 alpha-phorbol-12,13-didecanoate, produced no potentiation. The PE-induced potentiation was antagonized by the PKC inhibitor H-7. In addition, after 1 h exposure to PDBu (3 microM) and recovery from the potentiation (e.g. 2-4 h), a second exposure to PDBu or PDAc produced no potentiation. A 5 s 40 Hz supramaximal train to the CST produced a long lasting potentiation of the CAP (long-term potentiation, LTP) as described previously. However, a similar train did not evoke LTP after perfusion for 1 h with PDBu. The train-evoked LTP was depressed by the PKC inhibitor H-7 at a concentration which antagonized the PE-evoked potentiation. These data suggest that (i) PKC activation potentiates nicotinic transmission, and (ii) a component of the train-evoked LTP is mediated by PKC.
Action Potentials↗
The synaptic activation of NMDA receptors and Ca2+ signalling in neurons.
Long-term potentiation (LTP) in the hippocampus is a model system for understanding the synaptic basis of learning and memory. We have studied the mechanism of induction of LTP using voltage-clamp techniques and confocal imaging of Ca2+ in rat hippocampal slices. In the Schaffer collateral-commissural pathway the neurotransmitter L-glutamate activates two classes of ionotropic receptor, named after the selective ligands AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) and NMDA (N-methyl-D-aspartate). During low frequency transmission the excitatory postsynaptic potential (EPSP) is mediated predominantly by AMPA receptors. NMDA receptors play a minor role because their ion channels are substantially blocked by Mg2+, and this block is intensified by GABA-mediated synaptic inhibition. During high frequency transmission the GABA-mediated inhibition is depressed, by mechanisms initiated by GABAB autoreceptors. This allows a greater contribution from the NMDA receptors, through which Ca2+ enters the dendrites of the postsynaptic neurons to initiate a cascade of biochemical processes which ultimately result in enhanced synaptic efficiency.
Animals↗
Chronic treatment with lithium or desipramine alters discharge frequency and norepinephrine responsiveness of cerebellar Purkinje cells.
Cerebellar Purkinje cells were studied by electrophysiological techniques in rats treated chronically with either desipramine (DMI) or lithium chloride given intragastrically. A striking decrement occurred in discharge frequencies of simple spikes and climbing fiber bursts in both groups of animals, similar to the depression produced by iontophoresis of these agents. Chronic treatment with DMI markedly decreased responsiveness to iontophoretically applied norepinephrine (NE), whereas long-term LiCl therapy slightly enhanced response to NE; responses to gamma-aminobutyric acid were unchanged by these treatments. The inhibitory responses to locus ceruleus stimulation were unaffected by chronic LiCl treatment. The effects of these chronic treatments on responsiveness to NE are opposite to the effects these same drugs produce when administered by acute iontophoresis to single cells: DMI then potentiates and LiCl antagonizes noradrenergic responses. These results provide electrophysiological evidence for reciprocal adaptive changes in NE sensitivity, supporting results of biochemical studies.
Animals↗
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↗