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Results for “Long-Term Synaptic Depression”

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PubMed1978

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Phenoxybenzamine, FLA-63 and alpha-MT produced less locomotor depression in mice withdrawn for 4 days from a 21 day treatment with haloperidol than that produced in vehicle-treated animals.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↗

PubMed1979

[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↗

PubMed1991

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↗

PubMed1979

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↗

PubMed1992

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↗

PubMed1992

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↗

PubMed1992

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↗

PubMed1992

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↗

PubMed1991

Antidepressants affect amine modulation of neurotransmission in the rat hippocampal slice--I. Delayed effects.

The effects of long-term treatment with the antidepressant drugs, desipramine (DMI) and mianserin (MIA) on neurotransmission in the hippocampal slice were studied by examining the actions of serotonin (5-HT), isoprenaline and (+/-)-baclofen on the population spike in the pyramidal cell layer, recorded in area CA1. The decrease in amplitude of the population spike by 5-HT (1-10 microM) was facilitated by long-term treatment with DMI but not significantly with MIA. Both DMI and MIA depressed the excitatory action of isoprenaline (0.3 microM), whereas the inhibitory responses to (+/-)-baclofen (0.3-3 microM) were unaffected. The results show that significant changes in serotonergic and beta-adrenergic neurotransmission can be demonstrated ex vivo after in vivo treatment with antidepressants and that these changes partly substantiate data measured in vivo.

Adaptation, Physiological↗

PubMed1992

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↗

PubMed1991

Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine--I. Effects of acute and long-term administration of tandospirone on serotonin neurotransmission.

The acute and long-term effects of the antidepressant/anxiolytic selective 5-HT1A receptor ligand, tandospirone (SM-3997) on 5-HT neurotransmission were assessed using single-cell extracellular recording in chloral hydrate-anaesthetized rats. The acute intravenous administration of tandospirone decreased the firing rate of 5-HT neurones of the dorsal raphe (ED50 = 9.1 +/- 1.1 micrograms/kg). A treatment with tandospirone for 2 days (10 mg/kg/day, s.c.), markedly reduced the firing activity of 5-HT neurones of the dorsal raphe; this was followed by a partial recovery after 7 days and by complete recovery after 14 days of administration of tandospirone. After treatment with tandospirone for 14 days (10 mg/kg/day, s.c.), the responsiveness of 5-HT neurones to the intravenous administration of LSD was reduced, suggesting that somatodendritic 5-HT autoreceptors had desensitized. The depressant effects of microiontophoretically-applied tandospirone and 5-HT, on the firing activity of CA3 pyramidal neurones in the hippocampus were blocked by the intravenous injection of the 5-HT1A receptor antagonist, BMY-7378. The depressant effect of microiontophoretically-applied 5-HT onto these same neurones was markedly reduced during concurrent background application of tandospirone, suggesting that the latter acted as a partial agonist at postsynaptic 5-HT1A receptors. The sustained administration of tandospirone for 14 days (10 mg/kg/day, s.c.) altered neither the effectiveness of microiontophoretically-applied 5-HT and tandospirone nor that of endogenous 5-HT, released by the electrical simulation of the afferent 5-HT pathway, in suppressing the firing activity of pyramidal neurones in the hippocampus, suggesting that postsynaptic 5-HT1A receptors had not desensitized. Furthermore, long-term treatment with tandospirone did not alter the sensitivity of the terminal 5-HT autoreceptor. It is thus concluded that desensitization of somatodendritic 5-HT autoreceptors permits 5-HT neurones to regain their physiological rate of firing during long-term treatment with tandospirone and, consequently, to release a normal amount of 5-HT into the synaptic cleft. This, combined with the sustained activation of normosensitive postsynaptic 5-HT1A receptors by tandospirone, during such a treatment, should result in an enhanced tonic activation of postsynaptic 5-HT1A receptors.

Animals↗

PubMed1979

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↗

PubMed1991

Induction of long-term potentiation without participation of N-methyl-D-aspartate receptors in kitten visual cortex.

1. Intracellular recording was made from layer II-III cells in slice preparations of kitten (30-40 days old) visual cortex. Low-frequency (0.1 Hz) stimulation of white matter (WM) usually evoked an excitatory postsynaptic potential (EPSP) followed by an inhibitory postsynaptic potential (IPSP). The postsynaptic potentials (PSPs) showed strong dependence on stimulus frequency. Early component of EPSP and IPSP evoked by weak stimulation both decreased monotonically at frequencies greater than 0.5-1 Hz. Strong stimulation similarly depressed the early EPSP at higher frequencies (greater than 2 Hz) and replaced the IPSP with a late EPSP, which had a maximum amplitude in the stimulus frequency range of 2-5 Hz. 2. Very weak WM stimulation sometimes evoked EPSPs in isolation from IPSPs. The falling phase of the EPSP revealed voltage dependence characteristic to the responses mediated by N-methyl-D-aspartate (NMDA) receptors and was depressed by application of an NMDA antagonist DL-2-amino-5-phosphonovalerate (APV), whereas the rising phase of the EPSP was insensitive to APV. 3. The early EPSPs followed by IPSPs were insensitive to APV but were replaced with a slow depolarizing potential by application of a non-NMDA antagonist 6,7-dinitro-quinoxaline-2,3-dione (DNQX), indicating that the early EPSP is mediated by non-NMDA receptors. The slow depolarization was mediated by NMDA receptors because it was depressed by membrane hyperpolarization or addition of APV. 4. The late EPSP evoked by higher-frequency stimulation was abolished by APV, indicating that it is mediated by NMDA receptors, which are located either on the recorded cell or on presynaptic cells to the recorded cells. 5. Long-term potentiation (LTP) of EPSPs was examined in cells perfused with solutions containing 1 microM bicuculline methiodide (BIM), a gamma-aminobutyric acid (GABA) antagonist. WM was stimulated at 2 Hz for 15 min as a conditioning stimulus to induce LTP, and the resultant changes were tested by low-frequency (0.1 Hz) stimulation of WM. 6. LTP of early EPSPs occurred in more than one-half of the cells (8/13) after strong conditioning stimulation. The rising slope of the EPSP was increased 1.6 times on average. 7. To test involvement of NMDA receptors in the induction of LTP in the early EPSP, the effect of conditioning stimulation was studied in a solution containing 100 microM APV, which was sufficient to block completely synaptic transmission mediated by NMDA receptors. LTP occurred in the same frequency and magnitude as in control solution.

2-Amino-5-phosphonovalerate↗

PubMed1991

Inositol 1,4,5-trisphosphate 3-kinase distribution in the rat brain. High levels in the hippocampal CA1 pyramidal and cerebellar Purkinje cells suggest its involvement in some memory processes.

The distribution of inositol 1,4,5-trisphosphate (InsP3) 3-kinase was studied in the adult rat brain, using polyclonal antibodies raised against the purified 50,000-Da rat brain enzyme by immunohistochemistry and Western blot, in addition to enzymatic assay. Immunohistochemically, the enzyme was detected in neurons, where it was localized in the dendrites and at the periphery of the cell bodies. Using selective toxin lesions, the highest enzyme levels were found in the dendrites of hippocampal CA1 pyramidal cells and in neurons in the dorsal portion of the lateral septum, regions both involved in long-term potentiation; and in the dendrites of Purkinje cell subpopulations in the cerebellum, a region involved in long-term depression. High levels were found in neurons in the cortex; in the anterior olfactory nucleus; in the striatum (caudate, putamen, olfactory tubercle, Calleja islets and accumbens); in the central nucleus of the amygdala; in the hippocampal dentate gyrus and in the subiculum. The enzyme was not detected in other brain regions. By Western blot, a 50,000-Da immunoreactive band was present in the cortex, caudate-putamen and cerebellum. This band was most highly stained in the hippocampus. InsP3 3-kinase activity, stimulated by calcium/calmodulin, corresponded to 6172-2638 pmol of InsP4 produced/min/mg protein in the hippocampus followed by frontal and parietotemporal cortex and cerebellum. This activity was below 400 in the brainstem and spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)

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↗

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↗