Long-lasting potentiation produced by a phorbol ester in the hippocampus of the anaesthetized rat is not associated with a persistent enhanced release of excitatory amino acids (original) (raw)
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Phorbol esters enhance transmitter release in rat hippocampal slices
Brain Research, 1987
Phorbol esters enhance synapuc transmission in the rat hippocampal slice preparation most likely by acting at a presynaptic locus. To more directly examine the actions of phorbol esters on neurotransmitter release we have measured their effects on the occurrence of spontaneous postsynaptic potentials as well as on the potassium stimulated release of endogenous glutamate, Both measures of transmitter release were increased by phorbol esters suggesting a functional or regulatory role for protein kinase C in controlling the release of neurotransmitter in the mammalian CNS.
The Journal of physiology, 1993
1. The effects of phorbol esters on evoked and spontaneous excitatory neurotransmission were studied in the CA1 area in the in vitro hippocampal slice preparation of the rat. Experiments were conducted using field potential recording and whole-cell voltage clamp of CA1 pyramidal neurons. 2. Pyramidal cells dialysed during whole-cell recording with EGTA-containing electrode solutions, unable to support the induction of long-term potentiation (LTP), still showed robust phorbol ester-induced potentiation of excitatory synaptic transmission. 3. Spontaneous miniature excitatory postsynaptic currents (EPSCs), recorded in whole-cell voltage clamp in the presence of tetrodotoxin and picrotoxin, had amplitudes ranging from 4 to 40 pA and occurred at an average frequency of 0.8-5 Hz. Neither the amplitude nor the frequency of spontaneous EPSCs was altered by cadmium, dihydropyridines, or omega-conotoxin GVIA. 4. The phorbol ester 4-beta-phorbol 12,13-diacetate increased the frequency of spont...
Phorbol ester-induced synaptic facilitation is different than long-term potentiation
Proceedings of the National Academy of Sciences, 1988
The studies described here tested the hypothesis that the changes in synaptic efficacy produced by phorbol esters in hippocampal slices are equivalent to the long-term potentiation (LTP) induced by high-frequency stimulation. In contrast to the extremely stable synaptic potentiation induced by electrical stimulation, the facilitatory effects of phorbol 12,13-diacetate and phorbol 12,13-dibutyrate were transient: washout of the drugs restored normal responses in approximately 1-2 and 2-4 hr for phorbol diacetate and phorbol dibutyrate, respectively. It is noteworthy that the more liposoluble of the phorbol esters required longer washout periods. Robust LTP still occurred in response to high-frequency stimulation after washout of phorbol esters and to a lesser degree during their application. Treatment of slices with H-7, an inhibitor of protein kinase C, did not prevent LTP induction although it significantly affected neuronal excitability and produced effects opposite to those of ph...
Neuroscience, 1989
The relationship between long-term potentiation of synaptic transmission and the release of endogenous glutamate and aspartate has been investigated in the CA1 region of the hippocampus and in the fascia dentata of the anaesthetized rat. A high-frequency train of electrical stimulation of afferent pathways produced a long lasting (r2 h) enhancement of the field excitatory postsynaptic potential in CA1 and of the population spike in the fascia dentata. In both regions, this was not associated with a significant long lasting increase in the release of glutamate and aspartate. It is concluded that the maintenance of long-term potentiation is not associated with a sustained increase in the release of excitatory amino acids.
European Journal of Pharmacology, 1988
Enhancement of neurotransmitter release following phorbol ester-induced activation of protein kinase C (PKC) may be mediated by changes in ion conductance through the presynaptic membrane. This question was studied with rabbit hippocampal slices preincubated with [3H]noradrenaline ([3H]NA). NA release was evoked by pulses of either nigh K ÷ or Ca 2+ (in the presence of high K+), or by electrical field stimulation. 4fl-Phorbol 12,13-dibutyrate (PDB) increased and polymyxin B (PMB) reduced the K+-evoked NA release independent of the K ÷ concentration used for depolarization. The effects of PDB and PMB were not reduced by tetrodotoxin. PDB still enhanced the NA release triggered by short Ca 2+ pulses in depolarized, axon terminal membranes (30 mM K + and no Ca2+). The electrically evoked NA release was markedly enhanced by PDB even in the absence of C1-in the medium or in the presence of the K + channel blockers, tetraethylammonium, 4-amino-and 3,4-diaminopyridine. The inhibitory effect of the Ca 2+ channel blocker, Cd 2+, remained almost unchanged in the presence of PDB. It is concluded that PKC activation facilitates NA release in the nippocampus but not via presynaptic changes in Na +, K ÷ or C1-currents. Whether phorbol ester mediates an increased intracellular Ca 2+ availability, or whether a triggering 'normal' Ca 2÷ influx simply initiates, and synergistically supports, the PKC-mediated reactions leading to enhanced exocytosis, cannot be decided from the results of the present experiments.
Release of proteins during long-term potentiation in the hippocampus of the anaesthetized rat
Neuroscience Letters, 1988
Using a push pull device, the release of endogenous proteins in the cxtracellular space was investigated in the CAI region of the hippocampus of anaesthetized rats. With tow-frequency stimulation of the Schaffer collaterals, there was a relatively stable release of 5 proteins (64, 54, 48, 45 and 16 kDa). A train of high-frequency stimulation produced a long-lasting enhancement of the negative field EPSP and a delayed (90 120 min) enhancement of the release of these proteins. An additional 19 kDa protein was present only 90 min after the train. These observations raise the possibility that release of proteins might be involved in the maintenance of LTP. Long-term potentiation (LTP) is a long lasting enhancement of synaptic transmission produced by a train of high-frequency electrical stimulation [8, 28]. This phenomenon has been extensively studied in the hippocampal region and provides a useful experimental model for the study of the cellular mechanisms underlying learning and memory [20, 21]. However, the contribution of pre-and postsynaptic mechanisms to LTP have not been clarified; thus, there is a disagreement as to whether LTP is [9, 13, 15] or is not [4] associated with an increased release of the transmitter candidates glutamate or aspartate. Application of phorbol ester which produces LTP, different from that seen after a train [16], is also not associated with a release of endogenous excitatory amino acids [5]. Biochemical modifications in the hippocampus as well as protein phosphorylation have been reported after LTP [1, 2, 6, 11, 18, 23]. The appearance of newly synthesized proteins [14] in the extracellular fluid (ECF) and the prevention of LTP by inhibitors of protein synthesis [26] or monoclonal antibodies [27] suggest the involvement of macromolecules in this phenomenon. In the present study, using a push-pull cannula, we have examined the release of constituent proteins of the extracellular space
Phorbol Esters Potentiate Evoked and Spontaneous Release by Different Presynaptic Mechanisms
The Journal of Neuroscience, 2000
Phorbol esters enhance release from a variety of cell types. The mechanism by which phorbol esters potentiate presynaptic release from central neurons is unclear, although effects of phorbol esters both on the readily releasable pool of vesicles and on presynaptic calcium channels have been shown. Using confocal microscopy and the fluorescent styryl dye FM 1-43, we have examined the effects of phorbol-12,13-dibutyrate (PDBu) on presynaptic vesicle turnover at individually identified synapses in dissociated cultures obtained from neonatal rat hippocampus. Using different dye staining and destaining protocols we were able to resolve two effects of PDBu. Potentiation of evoked release by PDBu was insensitive to calcium channel antagonists, suggesting that this effect results from an increased number of vesicles in the readily releasable pool. Since we observed no effect of PDBu on the size of the total recycling vesicle pool, we conclude that phorbol esters alter the equilibrium betwee...
Phorbol Esters Enhance Neurotransmitter-Stimulated Cyclic AMP Production in Rat Brain Slices
Journal of Neurochemistry, 1986
The effect of phorbol esters on cyclic AMP production in rat CNS tissue was examined. Using a prelabeling technique for measuring cyclic AMP accumulation in brain slices, it was found that phorbol 12-myristate, 13-acetate (PMA) enhanced the cyclic AMP response to forskolin and a variety of neurotransmitter receptor stimulants while having no effect on second messenger accumulation itself. A short (15-min) preincubation period with PMA was required to obtain maximal enhancement, whereas the augmentation was lessened by prolonged exposure (3 h) to the phorbol. The response to PMA was concentration dependent (ECSo = 1 p M) and regionally selective, being most apparent in forebrain, and was not influenced by removal of extracellular calcium or by inhibition of phosphodiesterase or phospholipase A2. Only those phorbols known to stimu
European Journal of Pharmacology, 1989
We used rabbit hippocampus slices preincubated with [SH]noradrenaline (NA) and applied short pulses of 3,4-diaminopyridine (3,4-DAP) during superfusion to investigate the mechanism underlying the 3H overflow evoked by 3,4-DAP and the effects of the protein kinase C (PKC) activator, 4/3-phorbol 12,13-dibutyrate (PDB). in this model. The 3H overflow evoked by 200 ~M 3,4-DAP (about 4-5% of tissue-tritium) was largely Ca2+-dependent, tetrodotoxin-sensitive and markedly reduced by clonidine, but it was enhanced by yohimbine. We also demonstrated that the response could be inhibited via presynaptic adenosine (A1-) and opioid (K-) receptors. PDB (1 p,M) markedly increased the 3,4-DAP-evoked 3H overflow, its effect being almost unchanged following activation of presynaptic a2-, At-or ~-receptors. Inhibitors of PKC (polymyxin B, staurosporine) almost abolished the 3,4-DAP-evoked ~H overflow and antagonized the effects of PDB. It is concluded that application of 3,4-DAP (200 btM for 2 min) to brain slices leads to depolarization of the neuronal membrane, Na + current-carried action potentials, Ca 2+ influx and the exocytotic release of NA, which in many aspects resembles the release evoked by electrical field stimulation. The findings with phorbol ester further support the involvement of PKC in transmitter release. Activation of PKC apparently does not directly interfere with signal transduction mechanisms of presynaptic inhibitory receptors on noradrenergic nerve terminals.