Enhancement Of Synaptic Transmission Research Articles

Enhanced synaptic transmission and reduced threshold for LTP induction in fyn-transgenic mice.

To elucidate the physiological role of Fyn, we analysed the properties of synaptic transmission and synaptic plasticity in hippocampal slices of mice overexpressing either wild-type Fyn (w-Fyn) or its constitutively active mutant (m-Fyn). These fyn-transgenes were driven by the calcium/calmodulin-dependent protein kinase II alpha promoter which turned on in the forebrain neurons including hippocampal pyramidal cells and in late neural development. In the hippocampal slices expressing m-Fyn the paired-pulse facilitation was reduced and the basal synaptic transmission was enhanced. A weak theta-burst stimulation, which was subthreshold for the induction of long-term potentiation (LTP) in control slices, elicited LTP in CA1 region of the slices expressing m-Fyn. When a relatively strong stimulation was applied, the magnitude of LTP in m-Fyn slices was similar to that in control slices. By contrast, the basal synaptic transmission and the threshold for the induction of LTP were not altered in the slices overexpressing wild-type Fyn. To examine the effect of expression of m-Fyn on GABAergic inhibitory system, we applied bicuculline, a GABAA receptor blocker, to the hippocampal slices. The ability of bicuculline to enhance excitatory postsynaptic potentials was attenuated in slices expressing m-Fyn, suggesting that the overexpression of m-Fyn reduced the GABAergic inhibition. The enhancement of synaptic transmission and the reduction of GABAergic inhibition may contribute to the enhanced seizure susceptibility in the mice expressing m-Fyn. Thus, these results suggest that regulation of Fyn tyrosine kinase activity is important for both synaptic transmission and plasticity.

Action potential broadening induced by lithium may cause a presynaptic enhancement of excitatory synaptic transmission in neonatal rat hippocampus.

Lithium enhances excitatory synaptic transmission in CA1 pyramidal cells, but the mechanisms remain unclear. The present study demonstrates that lithium enhances the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid (AMPA) receptor-mediated components of the excitatory postsynaptic current (EPSC). Lithium decreased the magnitude of paired-pulse facilitation and presented an inverse correlation between the lithium-induced enhancement of synaptic transmission and initial paired-pulse facilitation, which is consistent with a presynaptic mode of action. The enhancement of synaptic strength is likely to act, at least in part, by increasing the amplitude of the presynaptic Ca2+ transient. One mechanism which could account for this change of the presynaptic Ca2+ transient is an increase in the duration of the action potential. We investigated action potential in hippocampal pyramidal neurons and found that lithium (0.5-6 mM) increased the half-amplitude duration and reduced the rate of repolarization, whereas the rate of depolarization remained similar. To find out whether the lithium synaptic effects might be explained by spike broadening, we investigated the field recording of the excitatory postsynaptic potential (EPSP) in hippocampal slices and found three lines of evidence. First, the prolongation of the presynaptic action potential with 4-aminopyridine and tetraethylammonium blocked or reduced the synaptic effects of lithium. Second, the lithium-induced synaptic enhancement was modulated when presynaptic Ca2+ influx was varied by changing the external Ca2+ concentration. Finally, both effects, the synaptic transmission increment and the action potential broadening, were independent of inositol depletion. These results suggest that lithium enhances synaptic transmission in the hippocampus via a presynaptic site of action: the mechanism underlying the potentiating effect may be attributable to an increased Ca2+ influx consequent to the broadening effect of lithium on the action potential.

Arachidonic acid metabolites and the synaptic potentiation evoked by activation of metabotropic glutamate receptors.

We have previously shown that coapplication of arachidonic acid (10 microM) and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD, 50 microM) evokes an enhancement of synaptic transmission in the CA1 region of the rat hippocampal slice. Here we have investigated whether the metabolites of arachidonic acid are implicated in this potentiation. Inclusion of the cyclo-oxygenase inhibitor indomethacin (10 microM) did not block the potentiation induced by coapplication of arachidonic acid and ACPD. However, the presence of either the cyclo-, lipo- and epoxygenase inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA, 20 microM), or the lipoxygenase inhibitor nordihydroguaiaretic acid (10 microM), prevented the long-lasting enhancement. The results suggest that the lipoxygenase and epoxygenase metabolites of arachidonic acid may be involved in the induction of this form of synaptic potentiation.

Enhancement of synaptic transmission by HPC-1 antibody in the cultured hippocampal neuron.

To clarify the function of HPC-1/syntaxin 1A in the mammalian central synapse, the effects of intracellularly applied antibody on the synaptic transmission were examined at the autapse of the cultured rat hippocampal neuron. Intracellularly applied antibody against HPC-1/syntaxin 1A (IgG, 0.3 mg ml(-1)) during whole-cell recording enhanced the autaptic excitatory postsynaptic current (EPSC). Pre-immune IgG (0.3 mg ml(-1)) showed no effect. The amplitude-distribution of an asynchronous EPSC was not affected by administration of this antibody, indicating that the increase in the amplitude of the evoked EPSC was attributable to an increase in transmitter release from the presynaptic terminal HPC-1/syntaxin 1A could be involved in suppressing as well as facilitating process of the exocytosis at the mammalian central synapse.

LTP in cingulate cortex of freely moving rats: duration and mGluR independence

The role of metabotropic glutamate receptors (mGluR) in synaptic transmission and plasticity of field potentials (fEPs) evoked by subicular stimulation of the cingulate cortex was investigated in freely moving adult rats. Tetanic stimulation with 100 Hz trains caused an enhancement of synaptic transmission in the cingulate cortex which lasted at least 24 hours, and can thus, be regarded as long-term potentiation (LTP). I.c.v. injection of the metabotropic glutamate receptor (mGluR) antagonist (R,S)-α-methyl-4-carboxyphenylglycine (MCPG) did not influence either baseline synaptic transmission or LTP of the fEPs. In contrast to the hippocampus mGluRs of the cingulate cortex seem not to be critically involved in the development of late LTP stages. © 1997 John Wiley & Sons, Ltd.

LTP in cingulate cortex of freely moving rats: duration and mGluR independence

The role of metabotropic glutamate receptors (mGluR) in synaptic transmission and plasticity of field potentials (fEPs) evoked by subicular stimulation of the cingulate cortex was investigated in freely moving adult rats. Tetanic stimulation with 100 Hz trains caused an enhancement of synaptic transmission in the cingulate cortex which lasted at least 24 hours, and can thus, be regarded as long-term potentiation (LTP). I.c.v. injection of the metabotropic glutamate receptor (mGluR) antagonist (R,S)-α-methyl-4-carboxyphenylglycine (MCPG) did not influence either baseline synaptic transmission or LTP of the fEPs. In contrast to the hippocampus mGluRs of the cingulate cortex seem not to be critically involved in the development of late LTP stages. © 1997 John Wiley & Sons, Ltd.

Poor correlation between postsynaptic [Ca] i increases and long-term potentiation induced by 2-deoxyglucose inCA1 hippocampal neurons

2-Deoxyglucose (2-DG; 10 mM) replacing glucose for ∼15 min regularly causes a very sustained enhancement of synaptic transmission in the CA1 hippocampal zone (2-DG-induced long-term potentiation, 2-DG-LTP). This LTP is prevented by dantrolene (10μM) or by the NMDA antagonist aminophosphonovalerate (APV; 50–100 μM); it is Ca-dependent [1, 2], and is not depressed by adenosine antagonists (DPCPX and 8-SPT), which prevent the initial block of EPSP caused by 2-DG, but is not observed if glucose is replaced by sucrose instead of 2-DG. To clarify the role of [Ca]i, in 2-DG-LTP, we monitored fluo-3 fluorescence inCA1 neurons, in submerged slices kept at 30°C. 2-DG applied as above consistently led to a rapid, but reversible rise in fluorescece. Isomodar sucrose (for 15–40 min) elicited smaller, but significant increases in fluorescence. Dantrolene and APV greatly reduced 2-DG's effect, but Ca-free medium did not abolish it. Paradoxically, it was fully suppressed by 8-SPT, but not at all by DPCPX. The discrepancies between the effects of sucrose and 8-SPT on the fluorescence changes and on 2-DG-LTP suggest that the observed increases in the postsynaptic [Ca] i are not essential for 2-DG-LTP. In further experiments, intracellular recordings showed that 2-DG applications consistently hyperpolarizeCA1 neurons, probably owing to adenosine-mediated activation of K+ conductance (which could be prevented by DPCPX or 8-SPT, but not by a KATP antagonist, glyburide). The 2-DG-LTP of EPSP was not suppressed by EGTA leakage from electrodes, in keeping with the above evidence that the [Ca] i changes needed for the induction of 2-DG-LTP are not those observed postsynaptically. In this respect, as well as in the absence of postsynaptic depolarization, 2-DG-LTP offers a marked contrast to more conventional forms of LTP.

340 Reduction of LTP threshold and enhancement of synaptic transmission in activated FYN mutant hippocampus

340 Reduction of LTP threshold and enhancement of synaptic transmission in activated FYN mutant hippocampus

Reduction of ltp threshold and enhancement of synaptic transmission in activated fyn mutant hippocampus

Reduction of ltp threshold and enhancement of synaptic transmission in activated fyn mutant hippocampus

Low-calcium-induced enhancement of chemical synaptic transmission from photoreceptors to horizontal cells in the vertebrate retina.

According to the classical calcium hypothesis of synaptic transmission, the release of neurotransmitter from presynaptic terminals occurs through an exocytotic process triggered by depolarization-induced presynaptic calcium influx. However, evidence has been accumulating in the last two decades indicating that, in many preparations, synaptic transmitter release can persist or even increase when calcium is omitted from the perfusing saline, leading to the notion of a "calcium-independent release" mechanism. Our study shows that the enhancement of synaptic transmission between photoreceptors and horizontal cells of the vertebrate retina induced by low-calcium media is caused by an increase of calcium influx into presynaptic terminals. This paradoxical effect is accounted for by modifications of surface potential on the photoreceptor membrane. Since lowering extracellular calcium concentration may likewise enhance calcium influx into other nerve cells, other experimental observations of "calcium-independent" release may be reaccommodated within the framework of the classical calcium hypothesis without invoking unconventional processes.

A comparison of the effects of two antispastic drugs, tizanidine and baclofen, on synaptic transmission from muscle spindle afferents to spinal interneurones in cats.

The alpha 2-adrenergic agonist tizanidine was reported to be more efficient than baclofen in reducing muscle tone in some spastic patients. The aim of this study was to investigate if this might be due to more specific depressive actions of tizanidine on transmission from muscle afferents which contribute to muscle tone. This was done by comparing the effects of tizanidine and baclofen on amplitudes of monosynaptic spinal focal field potentials produced by stimulation of muscle nerves in the cat. Such field potentials were recorded in the intermediate zone of the fourth lumbar segment, where they display two distinct components, an early one from group I afferents and a later one from group II afferents. Both reflect EPSPs produced in interneurones in disynaptic pathways to motoneurones. Tizanidine strongly depressed potentials caused by group II afferents, while it had no effect or slightly facilitated potentials produced by group I afferents. In contrast, baclofen had inconsistent effects on the group II potentials; in some cases it caused a depression and in others it caused only an increase in the latency and time to peak, at doses that strongly and consistently depressed the group I potentials. These effects have been found after both local and systemic applications. The antispastic actions of tizanidine may therefore only be related to the depression of transmission from group II muscle afferents, while antispastic actions of baclofen may be secondary to the depression of any sensory fibres. Since tizanidine is as effective in depressing spasticity as baclofen, it is suggested that the enhancement in synaptic transmission from group II muscle afferents may play an important role in the development of exaggerated stretch reflexes in spastic patients.

B-50 (GAP-43) in Onuf's nucleus of the adult cat

The nucleus of Onuf in the sacral spinal cord contains motoneurons that innervate the pelvic floor muscles and possess somatic and autonomic characteristics. We show in this study that in the intact adult cat, the immunocytochemical labelling of the nervous tissue-specific growth-associated protein, B-50 (GAP-43), which persists in Onuf's nucleus, differs markedly from that in the remaining ‘purely somatic’ motor nuclei of the sacral spinal cord. At the light microscopic level, an intense B-50 (GAP-43) immunoreactivity (B-50-IR) in the neuropil of Onuf's nucleus contrasts with a faint staining in the other spinal motor nuclei. Ultrastructurally, B-50-IR is found in Onuf's nucleus within some unmyelinated small diameter nerve fibres and numerous axon terminals on dendritic and somatic surfaces. Conversely, in all other motor nuclei only a few of these structures are stained. No other cellular profiles show B-50-IR in the tissue examined. According to the proposed functions of B-50 (GAP-43), its persistence in mature spinal axon terminals may indicate a latent capability of functional and structural remodeling, as well as an involvement in long-term enhancement in synaptic transmission. If so, these properties would be considerably more pronounce in Onuf's nucleus as compared to purely somatic motor nuclei.

Brief exposure to the G-protein activator NaF/AlCl3 induces prolonged enhancement of synaptic transmission in area CAl of rat hippocampal slices.

Rat hippocampal slices were exposed briefly (12-15 min) to AlF4- (10 mmol/l NaF, 10 mumol/l AlCl3). The effect on synaptic transmission in area CAl was measured using extracellular electrodes placed in the stratum pyramidale and stratum radiatum. During fluoride exposure, both spike and EPSP amplitude fell to very low levels. Upon washout, spike amplitude recovered beyond control values, and in half of the preparations a prolonged enhancement of spike amplitude (greater than 2 h) occurred. Similar modulation of EPSP slope indicated that these charges were primarily synaptic. If Al3+ was omitted from the F(-)-containing saline, enhancement of spike amplitude, when observed, was brief (20-30 min) and no enhancement of EPSP slope was seen. Omission of Ca2+ from the AlF(4-)-containing saline also abolished any long-lasting enhancement of synaptic transmission, though population spike amplitude in most slices showed a brief (20-30 min) stimulatory response. In preparations in which LTP had previously been saturated, synaptic transmission was not enhanced by exposure to AlF4-. It is concluded that NaF/ACl3 exposure induces an LTP-like process by G-protein activation, which involves recruitment of processes involved in LTP, possibly including an enhancement of Ca(2+)-influx.

A phorbol diester‐induced enhancement of synaptic transmission in olfactory cortex

1. Extracellular field synaptic potentials were recorded from pial surface slices of guinea-pig olfactory cortex maintained in vitro. 2. Phorbol 12,13-dibutyrate (0.1-10 microM) enhanced the amplitude of the evoked potential (by 51.2 +/- 10.4% with 1 microM) in normal solution. When the evoked potential was partially depressed by Cd, Co, Mn or a reduced Ca concentration, phorbol 12,13-dibutyrate (1 microM) induced a much larger enhancement of the evoked potential (196.5 +/- 24.4% increase). Phorbol 12,13-diacetate and mezerein had similar effects but were less potent. 4 beta-Phorbol (10 microM) had no effect. 3. The diacylglycerol analogues, dioctanoylglycerol (100-1000 microM), 1-oleoyl-2-acetylglycerol (100-500 microM) or diolein (100 microM) had no effect on the evoked potentials, either alone or in the presence of Cd. 4. The isoquinolinylsulphonamide inhibitor (H-7) of protein kinase C slightly enhanced the e.p.s.p. and had no effect on the potentiation produced by phorbol ester. Another protein kinase C inhibitor, acridine orange (100-1000 microM), had no effect on the action of phorbol ester. 5. These results show that transmitter release, as at other synapses, is enhanced by phorbol esters but Ca did not potentiate this action. The pharmacological profile of the effect on transmitter release differed from that of protein kinase C in cell-free preparations and therefore it is unclear whether protein kinase C was involved in the present study.

Effects of 4-aminopyridine on the action potential and the after-hyper polarization of cat spinal motoneurons

In cats under pentobarbital anaesthesia, intramotoneuronal administrations of 4-aminopyridine significantly prolong the falling phase of the antidromic action potential but have much less effect on the orthodromic action potential. 4-aminopyridine probably blocks the fast K channels involved in the repolarization of the membrane and indirectly activates ionic channels through enhancement of synaptic transmission, also suggested by the potentiation of excitatory postsynaptic potentials. In many cells, 4-aminopyridine depresses the amplitude and prolongs the time course of the after-hyperpolarization; therefore 4-aminopyridine may also partly block Ca2+-activated K+ channels.

Kindling-like stimulus patterns induce epileptiform discharges in the guinea pig in vitro hippocampus

In the guinea pig in vitro hippocampal slice preparation, we have demonstrated that the repeated tetanic stimulation of the Schaffer collateral-commissural input to CA1 pyramidal neurones produces a progressive increase in the amplitude and duration of postsynaptic potentials, and stimulus-induced and spontaneous paroxysmal depolarization shifts (PDSs). Both the enhancement of synaptic transmission and the genesis of PDSs were reversibly blocked by the N-methyl- d-aspartate (NMDA) receptor antagonist (±)-2-amino-5-phosphonovalerate (APV). These results provide evidence that progressive, stimulation-induced long-term potentiation may serve as the trigger for kindling-induced epileptogenesis, and this process is dependent on the repeated activation of an APV-sensitive receptor.

Hippocampal slices of kindled rats reveal calcium involvement in epileptogenesis.

Daily repeated tetanic electrical stimulation (kindling) of the brain may cause a long term enhancement of synaptic transmission and epileptiform activity of progressive severity and generalisation, eventually leading to spontaneous seizures. Evidence for a cellular mechanism underlying kindling has been obtained in vitro in slices from the hippocampus of kindled rats. A marked enhancement in extracellular calcium changes, induced by electrical stimulation or by iontophoresis of excitatory aminoacids was found in kindled tissue. This implies that changes in dendritic calcium conductances are involved in kindling epileptogenesis.

Enhancement of synaptic transmission by 4-aminopyridine in hippocampal slices of the rat.

1. The effects of 4-aminopyridine (4-AP) on neurotransmission in hippocampal slices of the rat were studied in vitro. 2. Extracellular recordings of field potentials and intracellular recordings of excitatory and inhibitory post-synaptic potentials, action potentials and TTX-resistant spikes were obtained from the somatic and dendritic fields of CA 1 hippocampal neurones. 3. Constant perfusion with, or bolus injection of 4-AP in micromolar concentrations resulted in substantial and persistent enhancement of the amplitude of synaptic field potentials and population spikes with no alteration of the afferent input. Somatic positive waves (p-waves) were increased with local micro-application of 4-AP. 4. Intracellular recordings revealed an increase in the amplitude of e.p.s.p.s. and i.p.s.p.s. I.p.s.p.s were prolonged by 4-AP. 5. The pyramidal cells were, after an initial hyperpolarization, depolarized by up to 10 mV during exposure to 4-AP; the membrane conductance was not consistently changed. 6. Spontaneous shifts of the membrane potential were described as giant e.p.s.p.s and i.p.s.p.s. Spontaneous i.p.s.p.s were increased in frequency and amplitude. 7. Paired-pulse facilitation of e.p.s.p.s was reduced by 4-AP suggesting a presynaptic modulation of transmitter output. 8. It is concluded that 4-AP enhances transmitter release at both excitatory and inhibitory synapses in the hippocampus.

Periodic fluctuations in synaptic transmission and enhancement of transmission in hippocampal slices

The properties of the synchronously activated radiatum fiber-CA1 synaptic population were examined with the in vitro hippocampal slice preparation. Periodic fluctuations in synaptic transmission and in the enhancement of synaptic transmission were observed with periods ranging from 8 to 20 s. Such periodic fluctuations did not arise from fluctuations in afferent radiatum fiber activity. The period and amplitude of the cyclic variations in the enhancement of synaptic transmission were found to be altered with repeated electrical stimulation of the radiatum fibers. These results reflect cooperative synaptic actions which must be taken into consideration in the delineation of the mechanisms of potentiation.

Enhancement of synaptic transmission by dendritic potentials in chromatolysed motoneurones of the cat.

1. Monosynaptic transmission in cat lumbosacral motoneurones undergoing chromatolysis was studied by intracellular recording from 7 to 20 days after section of the appropriate ventral roots.2. The average input resistance measured by passing polarizing currents across the cell membrane showed no significant difference between normal and chromatolysed motoneurones. Average rheobasic current for chromatolysed motoneurones was significantly lower (by about 30%) than that for normal motoneurones.3. Spike-like partial responses were commonly superimposed on monosynaptic EPSPs in chromatolysed motoneurones. These responses could be eliminated by stimulation of the bulbar inhibitory reticular formation, but could not be blocked by hyperpolarization applied to the motoneurone soma.4. The spike-like partial response in chromatolysed motoneurones showed a refractory period following (i) the antidromic invasion of the neurone generated by ventral root stimulation, and (ii) in response to two successive afferent stimuli. The refractory period ranged from 5 to 13 msec.5. Initiation of the partial response had no direct relation with the amplitude of the underlying EPSP. The partial response could be evoked by small EPSPs of about 0.5 mV.6. The action potential of a chromatolysed motoneurone arose from the partial response at different levels of depolarization, showing multiple trigger zones for spike initiation. Occasionally, chromatolysed motoneurones discharged in response to stimulation of a single afferent fibre.7. In neurones where more than one spike-like response was obtained, interaction between dendritic responses showed no refractoriness.8. It is concluded that the partial response is an all-or-none event originating at some discrete site on dendrites, and that its presence increases the efficacy of synaptic excitation in chromatolysed motoneurones.