Long-lasting Potentiation Of Synaptic Transmission Research Articles

Caffeine-induced synaptic potentiation in hippocampal CA2 neurons

Caffeine enhances cognition, but even high non-physiological doses have modest effects on synapses. A1 adenosine receptors (A1Rs) are antagonized by caffeine and are most highly enriched in hippocampal CA2, which has not been studied in this context. Here we show that physiological doses of caffeine in vivo or A1R antagonists in vitro induce robust, long-lasting potentiation of synaptic transmission in rat CA2 without effect in other regions of the hippocampus.

A new role for photoresponsive neurons called simple photoreceptors in the sea slug Onchidium verruculatum: Potentiation of synaptic transmission and motor response

The simple photoreceptors Ip-1 and Ip-2 are intrinsically light-sensitive neurons that exist in the abdominal ganglion of the sea slug Onchidium verruculatum. Using isolated ganglia and semi-intact or intact animal preparations, the present studies examined the light-sensing and physiological roles of Ip-1 and Ip-2 cells, which respond jointly to light by inducing a slow hyperpolarizing receptor potential. First, the synaptic inputs received by Ip-1 and Ip-2 and the axonal branches arising from their cell bodies were investigated. We found that these cells are not only first-order photosensory neurons, but also second-order neurons (interneurons), relaying inhibitory synaptic inputs such as water pressure and/or tactile senses. The amphibian Onchidium opens a pneumostome at low tide in order to aero-breathe. This pneumostome opening; i.e., aero-breathing behavior, was produced by spike discharges of Ip-1 and Ip-2 cells. Furthermore, the present results suggested that the hyperpolarizing photoresponse of Ip-1 and Ip-2 cells operates in the potentiation of inhibitory sensory synaptic transmission. Thus, we conclude that the simple photoreceptors of Onchidium play a role in the long-lasting potentiation of synaptic transmission and the subsequent behavioral response and so may be involved in a new photosensory modality, non-image-forming vision.

A new photosensory function for simple photoreceptors, the intrinsically photoresponsive neurons of the sea slug Onchidium

Simple photoreceptors, namely intrinsically light-sensitive neurons without microvilli and/or cilia, have long been known to exist in the central ganglia of crayfish, Aplysia, Onchidium, and Helix. These simple photoreceptors are not only first-order photosensory cells, but also second-order neurons (interneurons), relaying several kinds of sensory synaptic inputs. Another important issue is that the photoresponses of these simple photoreceptors show very slow kinetics and little adaptation. These characteristics suggest that the simple photoreceptors of the Onchidium have a function in non-image-forming vision, different from classical eye photoreceptors used for cording dynamic images of vision. The cited literature provides evidence that the depolarizing and hyperpolarizing photoresponses of simple photoreceptors play a role in the long-lasting potentiation of synaptic transmission of excitatory and inhibitory sensory inputs, and as well as in the potentiation and the suppression of the subsequent behavioral outputs. In short, we suggest that simple photoreceptors operate in the general potentiation of synaptic transmission and subsequent motor output; i.e., they perform a new photosensory function.

Octopus Conditioning: A Multi-Armed Approach to the LTP–Learning Question

A recent study shows that avoidance conditioning in the cephalopod Octopus vulgaris is mediated by long-term potentiation (LTP), a form of synaptic plasticity thought to be important in vertebrate associative learning. Thus, LTP appears to be an evolutionarily conserved learning mechanism.

α-Synuclein produces a long-lasting increase in neurotransmitter release

Wild-type alpha-synuclein, a protein of unknown function, has received much attention because of its involvement in a series of diseases that are known as synucleinopathies. We find that long-lasting potentiation of synaptic transmission between cultured hippocampal neurons is accompanied by an increase in the number of alpha-synuclein clusters. Conversely, suppression of alpha-synuclein expression through antisense nucleotide and knockout techniques blocks the potentiation, as well as the glutamate-induced increase in presynaptic functional bouton number. Consistent with these findings, alpha-synuclein introduction into the presynaptic neuron of a pair of monosynaptically connected cells causes a rapid and long-lasting enhancement of synaptic transmission, and rescues the block of potentiation in alpha-synuclein null mouse cultures. Also, we report that the application of nitric oxide (NO) increases the number of alpha-synuclein clusters, and inhibitors of NO-synthase block this increase, supporting the hypothesis that NO is involved in the enhancement of the number of alpha-synuclein clusters. Thus, alpha-synuclein is involved in synaptic plasticity by augmenting transmitter release from the presynaptic terminal.

Chemically-induced long-term potentiation in rat motor cortex involves activation of extracellular signal-regulated kinase cascade

The involvement of the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade in long-lasting potentiation of synaptic transmission, induced by tetraethylammonium (TEA) or by elevated extracellular calcium concentration, was investigated in layer V horizontal connections within motor cortex in rat brain slices. Brief application of TEA (25 mM) resulted in a long-lasting potentiation of field potentials by 54±12%. A transient exposure of slices to elevated extracellular calcium (5 mM) induced long-lasting potentiation of responses reaching 30±8%. The induction of both forms of potentiation was prevented by the exposure of slices to inhibitors of the upstream activator of ERK 1/2, MEK (ERK kinase), U0126 (20 μM) and PD 98059 (50 μM). PhosphoERK2 immunoreactivity was transiently increased above baseline levels 15 min after termination of the exposure of slices to either TEA or elevated calcium concentration. Both forms of potentiation were partially occluded by Sp-adenosine 3′,5′-cyclic monophosphorothioate triethylammonium salt (Sp-cAMPS; 100 μM), an activator of cAMP-dependent protein kinase (PKA), and they were blocked after preincubation with Rp-adenosine 3′,5′-cyclic monophosphorothioate triethylammonium salt (Rp-cAMPS; 100 μM), a specific inhibitor of PKA activation by cAMP. It has previously been shown that TEA-induced potentiation represents a N-methyl- d-aspartate (NMDA) receptor-independent form of persistent synaptic enhancement, and, on the contrary, calcium-induced potentiation depends on NMDA receptors. Thus, the activation of PKA and the ERK1/2 cascade are required for two forms of chemically induced long-lasting increases of synaptic efficacy in slices of rat motor cortex.

Potentiation of Hippocampal Synaptic Transmission by Superoxide Requires the Oxidative Activation of Protein Kinase C

Recent evidence suggests that reactive oxygen species (ROS), including superoxide, are not only neurotoxic but function as small messenger molecules in normal neuronal processes such as synaptic plasticity. Consistent with this idea, we show that brief incubation of hippocampal slices with the superoxide-generating system xanthine/xanthine oxidase (X/XO) produces a long-lasting potentiation of synaptic transmission in area CA1. We found that X/XO-induced potentiation was associated with a persistent superoxide-dependent increase in autonomous PKC activity that could be isolated via DEAE column chromatography. The X/XO-induced potentiation was blocked by the inhibition of PKC, indicating that the superoxide-dependent increase in autonomous PKC activity was necessary for the potentiation. We also found that X/XO-induced potentiation and long-term potentiation (LTP) occluded one another, suggesting that these forms of plasticity share similar cellular mechanisms. In further support of this idea, we found that a persistent, superoxide-dependent increase in autonomous PKC activity isolated via DEAE column chromatography also was associated with LTP. Taken together, our findings indicate that X/XO-induced potentiation and LTP share similar cellular mechanisms, including superoxide-dependent increases in autonomous PKC activity. Finally, our findings suggest that superoxide, in addition to its well known role as a neurotoxin, also can be considered a small messenger molecule critical for normal neuronal signaling.

Rapid increase in clusters of presynaptic proteins at onset of long-lasting potentiation.

A change in the efficiency of synaptic communication between neurons is thought to underlie learning. Consistent with recent studies of such changes, we find that long-lasting potentiation of synaptic transmission between cultured hippocampal neurons is accompanied by an increase in the number of clusters of postsynaptic glutamate receptors containing the subunit GluR1. In addition, potentiation is accompanied by a rapid and long-lasting increase in the number of clusters of the presynaptic protein synaptophysin and the number of sites at which synaptophysin and GluR1 are colocalized. These results suggest that potentiation involves rapid coordinate changes in the distribution of proteins in the presynaptic neuron as well as the postsynaptic neuron.

Induction of Mossy Fiber→CA3 Long-Term Potentiation Requires Translocation of Synaptically Released Zn2+

The mammalian CNS contains an abundance of chelatable Zn(2+) sequestered in the vesicles of glutamatergic terminals. These vesicles are particularly numerous in hippocampal mossy fiber synapses of the hilar and CA3 regions. Our recent observation of frequency-dependent Zn(2+) release from mossy fiber synaptic terminals and subsequent entry into postsynaptic neurons has prompted us to investigate the role of synaptically released Zn(2+) in the induction of long-term potentiation (LTP) in field CA3 of the hippocampus. The rapid removal of synaptically released Zn(2+) with the membrane-impermeable Zn(2+) chelator CaEDTA (10 mm) blocked induction of NMDA receptor-independent mossy fiber LTP by high-frequency electrical stimulation (HFS) in rat hippocampal slices. Mimicking Zn(2+) release by bath application of Zn(2+) (50-100 microm) without HFS induced a long-lasting potentiation of synaptic transmission that lasted more than 3 hr. Moreover, our experiments indicate the effects of Zn(2+) were not attributable to its interaction with extracellular membrane proteins but required its entry into presynaptic or postsynaptic neurons. Co-released glutamate is also essential for induction of LTP under physiological conditions, in part because it allows Zn(2+) entry into postsynaptic neurons. These results indicate that synaptically released Zn(2+), acting as a second messenger, is necessary for the induction of LTP at mossy fiber-->CA3 synapses of hippocampus.

Brain-derived neurotrophic factor induces long-lasting potentiation of synaptic transmission in visual cortex in vivo in young rats, but not in the adult.

Brain-derived neurotrophic factor (BDNF) rapidly enhances excitatory synaptic transmission in cortical slices. To date, however, a question of how long such an action persists remains unanswered as it is hard to record synaptic responses longer than several hours in slice preparations. To address this question and to investigate possible age-dependency of the action, we analysed effects of a brief application of BDNF and nerve growth factor (NGF) on field potentials of visual cortex in rats of postnatal days 13-17 and 19-24 and in the adulthood for 10-24 h. Evoked potentials to stimulation of the lateral geniculate nucleus were recorded simultaneously from two cortical sites into which the neurotrophin and control solution were injected. An application of BDNF induced a slowly developing increase in the field potential amplitude in young rats. The amplitude attained a plateau level 3-4 h after the infusion; 139 +/- 26% (mean +/- SD) and 132 +/- 21% of the baseline in the rats at P13-17 and P19-24, respectively. This potentiation remained stable from 4 to 8 h, then gradually decreased to the baseline 15-16 h after the infusion. NGF applied in the same way did not induce potentiation. An inhibitor of BDNF receptors blocked the potentiation when it was applied immediately after the BDNF application, but was not effective about 2 h later. In the adults, BDNF did not potentiate field potentials. These results indicate that BDNF induces synaptic potentiation lasting for several hours only in the developing cortex through processes downstream of receptor activation.

Effects of low-frequency tetanic stimulation of the synaptic inputs on different forms of long-term potentiation in the rat hippocampus

In experiments on transversal slices of the dorsal hippocampus of rats, we found that low-frequency stimulation of the mossy fibers (MF) against the background of pre-settled long-term post-tetanic potentiation in the MF-CA3 pyramidal neuron (PN) dendrites synaptic system evoked depotentiation in all studied slices. Depotentiation was considerably decreased by a non-competitive blocker of the NMDA glutamate receptors, ketamine (100 μM), as well as by an inhibitor of calmodulin, trifluoroperazine (10 μM), and an inhibitor of calcineurin, cyclosporin A (250 μM). At the same time, depontentiation was not changed by 50 μM polymixin B, an inhibitor of protein kinase C. Long-term potentiation of synaptic transmission in the Schaffer collaterals (SchC)-CA1 PN dendrites system, which was evoked by 2.5-min-long anoxia/aglycemia episodes, resulted exclusively from enhancement of the NMDA component of population EPSP, while their AMPA component was not modified, i.e., in this case potentiation was of a postsynaptic nature. Under these conditions, low-frequency stimulation of SchC resulted in a further increase in the intensity of synaptic transmission due to increases in both the NMDA and AMPA components of population EPSP. The above form of potentiation could be suppressed by 100 μM ketamine, 10 μM trifuoroperazine, 250 μM cyclosporin A, or 10 μM N-nitro-L-arginine. Weak (near-threshold) high-frequency stimulation of SchC induced long-lasting potentiation of synaptic transmission due to an isolated increase in the AMPA component of population EPSP, i.e., this potentiation was of a postsynaptic nature. In the latter case, low-frequency SchC stimulation resulted in further facilitation of synaptic transmission. Intensive tetanic high-frequency stimulation of the above fibers induced long-term potentiation of a presynaptic nature, while their low-frequency stimulation depotentiated synaptic transmission.

Potentiation of synaptic transmission by (S)-3,5-dihydroxy phenylglycine in the rat dentate gyrus in vitro: A role for voltage dependant calcium channels and protein kinase C

1. 1. The authors have previously shown that direct activation of metabotropic glutamate receptors (mGluRs) by (S)-3,5-dihydroxyphenylglycine ((S)-DHPG) can induce a long-lasting potentiation of synaptic transmission in the rat dentate gyrus in vitro. Here the authors provide further characterisation of this agonist-induced potentiation. 2. 2. Field excitatory post-synaptic potentials were recorded from the dentate gyrus of rat hippocampal slices prepared by standard methods. 3. 3. (S)-DHPG (40 μM) induced a significant potentiation of the field EPSP slope (148. 6 ± 4. 3% compared to controls, n = 5), which occluded tetanically-induced LTP. 4. 4. This potentiation was inhibited by the PKC inhibitors staurosporine (0. 1 μM) and H-7 (100 μM) and by the voltage dependent Ca 2+ channel (VDCC) blockers NiCl 2 (50 μM) and nifedipine (20 μM). 5. 5. The mGluR5 specific agonist (RS)-2-Chloro-5-Hydroxyphenylglycine (CHPG) did not induce a potentiation when applied to slices at concentrations from 20 μM to 1 mM indicating that the (S)-DHPG potentiation may be mediated through group I subtype 1 mGluRs. 6. 6. In conclusion the (S)-DHPG-induced potentiation observed in our studies may be PKC dependent and is likely to be mediated through both T/L subtype VDCC and mGluR1 subtype receptors.

Vasopressin-induced calcium signaling in cultured cortical neurons

Earlier autoradiographic studies from our laboratory detected vasopressin recognition sites in the mammalian cerebral cortex [R.E. Brinton, K.W. Gee, J.K. Wamsley, T.P. Davis, H.I. Yamamura, Regional distribution of putative vasopressin receptors in rat brain and pituitary by quantitative autoradiography, Proc. Natl. Acad. Sci. U.S.A., 81 (1984) 7248–7252; C. Chen, R.D. Brinton, T.J. Shors, R.F. Thompson, Vasopressin induction of long-lasting potentiation of synaptic transmission in the dentate gyrus, Hippocampus, 3 (1993) 193–204]. More recently, we have detected mRNA for the V1a vasopressin receptors (V1aRs) in cultured cortical neurons [R.S. Yamazaki, Q. Chen, S.S. Schreiber, R.D. Brinton, V1a Vasopressin receptor mRNA expression in cultured neurons, astroglia, and oligodendroglia of rat cerebral cortex, Mol. Brain Res., 45 (1996) 138–140]. To determine whether these recognition sites are functional receptors, we have pursued the signal transduction mechanism associated with the V1a vasopressin receptor in enriched cultures of cortical neurons. Results of these studies demonstrate that exposure of cortical neurons to the selective V1 vasopressin receptor agonist, [Phe 2,Orn 8]-vasotocin, (V 1 agonist) induced a significant accumulation of [ 3 H] inositol-1-phosphate ( [ 3 H] IP 1). V 1 agonist-induced accumulation of [ 3 H] IP 1 was concentration dependent and exhibited a linear dose response curve. Time course analysis of V 1 agonist-induced accumulation of [ 3 H] IP 1 revealed a significant increase by 20 min which then decreased gradually over the remaining 60 min observation period. V 1 agonist-induced accumulation of [ 3 H] IP 1 was blocked by a selective V1a vasopressin receptor antagonist, (Phenylac 1, d-Tyr(Me) 2, Arg 6,8, Lys-NH 2 9)-vasopressin. Results of calcium fluorometry studies indicated that V 1 agonist exposure induced a marked and sustained rise in intracellular calcium which was abolished in the absence of extracellular calcium. The loss of the rise in intracellular calcium was not due to a failure to induce PIP 2 hydrolysis since activation of the phosphatidylinositol pathway occurred in the absence of extracellular calcium. V 1 agonist activation of calcium influx was then investigated. V 1 agonist-induced 45 Ca 2+ uptake was concentration dependent with a biphasic time course. Preincubation with the L-type calcium channel blocker, nifedipine, blocked V 1 agonist-induced calcium influx suggesting V 1 agonist-induced L-type calcium channel activation in cortical neurons. Furthermore, V 1 agonist-induced calcium influx was blocked by both bisindolyleimide I (PKC inhibitor) and U-73122 (PLC inhibitor) suggesting a modulation of V 1 agonist-induced L-type calcium channel activation by downstream components of the phosphatidylinositol signaling pathway such as protein kinase C. These results indicate that in cultured cortical neurons, V1a vasopressin receptor activation leads to induction of the phosphatidylinositol signaling pathway, influx of extracellular calcium via L-type calcium channel activation, and a rise in intracellular calcium which is dependent on V1a receptor activated influx of extracellular calcium. These data are the first to demonstrate an effector mechanism for the V 1 vasopressin receptor in the cerebral cortex and provide a potential biochemical mechanism that may underlie vasopressin enhancement of memory function.

Taurine-induced potentiation is partially reversed by low-frequency synaptic stimulation.

Neuroinhibitory actions of taurine in the brain are well known to be mediated by the activation of GABAA receptors11. We have recently reported a new neuromodulatory taurine action in the hippocampus independent of this GABA receptor type8,9. The new taurine action consists of a long-lasting potentiation of synaptic transmission, that is induced when taurine is applied at a concentration of 5–10 mM over a 10–30 min period. Excitatory postsynaptic potentials (EPSP) increase during taurine application, remaining elevated long after taurine withdrawal (at least three hours). This new taurine action could have important relevance to brain function, since persistent changes in the synaptic strength are envisaged as the cellular substrate of learning and memory4. Taurine-induced potentiation, unlike long-term potentiation (LTP) induced by high frequency synaptic stimulation of afferent fibers, is independent of NMDA receptor activation8. Nevertheless, taurine-induced potentiation has some points in common with LTP, primarily because its induction requires a rise in intracellular calcium, and both potentiation phenomena occlude mutually (Del Olmo et al., in preparation).

Block of induction and maintenance of calcium-induced LTP by inhibition of protein kinase C in postsynaptic neuron in hippocampal CA1 region

Calcium-induced LTP (Ca-LTP) refers to the long-lasting potentiation of synaptic transmission in hippocampal synapses that can be induced by a transient (7–10 min) and small increase (from 2 mM to 4 mM) in extracellular calcium concentration. In this paper the effects of protein kinase C (PKC) inhibitors, polymyxin B (PMB) and PKC(19–31), given intracellularly to the postsynaptic neuron in the CA1 region, on the induction and maintenance of Ca-LTP were studied and compared with those found in a similar study earlier made in this laboratory on tetanic stimulation-induced LTP (TS-LTP) [18]. When the intracellular delivery of the inhibitor(s) was made to begin 30 min before the exposure to increased [Ca 2+] 0, the development of Ca-LTP was completely blocked, leaving only a brief enhancement of EPSPs directly attributable to the brief increase in [Ca 2+] 0. When the intracellular delivery of either PKC(19–31) alone or PMB + PKC(19–31) was made to begin after the full establishment of Ca-LTP, it soon made the maintained potentiation begin to decline, the EPSP amplitude gradually returning to the control value before the exposure to increased calcium. Thus postsynaptic PKC inhibition blocks both the induction and the maintenance of Ca-LTP, just as it has been shown to do to TS-LTP. But quantitative differences exist: both the induction and the maintenance of Ca-LTP appeared to be more susceptible to block by postsynaptic PKC inhibition than those of TS-LTP.

Characterisation of LTP induced by the activation of glutamate metabotropic receptors in area CA1 of the hippocampus

The transient activation of the N- methyl- D- aspartate (NMDA) receptor system by high frequency (tetanic) stimulation results in a rapidly developing and long-lasting potentiation of synaptic transmission in the CA1 region of the hippocampus. This potentiation can be divided into an early decremental component, known as short-term potentiation (STP), and a more slowly developing persistent phase, termed long-term potentiation (LTP). Here we described how activation of metabotropic glutamate receptors (mGluRs), by aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD), can induce the same stable form of LTP, but without the STP component. 1S,3R-ACPD-induced LTP does not require electrical stimulation during its induction, but is dependent on an intact connection between the CA3 and CA1 regions of the hippocampus. 1S,3R-ACPD-induced LTP circumvents the need for the activation of NMDA receptors and is likely to involve both the stimulation of protein kinase C (PKC) and the release of Ca 2+ from intracellular stores.

1401 A phosphatase inhibitor induces long-lasting potentiation of synaptic transmission in the hippocampal CA1 region

1401 A phosphatase inhibitor induces long-lasting potentiation of synaptic transmission in the hippocampal CA1 region

Long-term potentiation of hippocampal synaptic transmission affects rate of behavioral learning.

Electrical stimulation techniques were used to produce a long-lasting potentiation of synaptic transmission in the hippocampus of naïve rabbits. Animals were then classically conditioned. Long-term potentiation of the hippocampus before training increased the rate at which animals subsequently learned the conditioning task. This result has significance for potential cellular mechanisms of associative learning.

Facilitated induction of hippocampal long-lasting potentiation during blockade of inhibition.

A long-lasting potentiation of synaptic transmission can be induced in the hippocampus by high-frequency stimulation of the afferent fibres1,2. This process has been regarded as a possible physiological substrate for long-term memory. From theoretical considerations on memory function it has been proposed that synaptic strengthening occurs as a result of simultaneous pre- and postsynaptic activation3, a principle which has been used in several theoretical models (for references see refs 4, 5). It thus seems important to study factors which control hippocampal long-lasting potentiation and, in particular, whether these factors act pre- or postsynaptically. A presynaptic control of long-lasting potentiation was established in experiments where two separate inputs to the same population of CA1 pyramidal cells were used6,7. Studies on the granule cell population of area dentata however, revealed, a heterosynaptic modulation of the generation of potentiation, suggesting a possible postsynaptic control also8,9. We have now studied long-lasting potentiation in the hippocampal slice preparation (CA1 region) in conditions where postsynaptic inhibition was reduced by application of γ-aminobutyric acid (GABA) receptor blockers. We found that in addition to their direct effect on inhibition, GABA blockers dramatically facilitated the induction of long-lasting potentiation. The results indicate involvement of postsynaptic mechanisms in the generation of long-lasting potentiation.

Possible mechanisms for long-lasting potentiation of synaptic transmission in hippocampal slices from guinea-pigs.

1. Long-lasting potentiation of synaptic transmission was studied in the CA1 region of guinea-pig hippocampal slices maintained in vitro. 2. Stimulating pulses were delivered alternately to two independent afferent pathways, stratum radiatum and stratum oriens. The presynaptic volleys and field e.p.s.p.s. were recorded from the same two layers, while an electrode in the pyramidal cell body layer recorded the population spike or in other experiments the extra- or intracellular potentials from a single pyramidal cell. 3. A short tetanus to either of the two input pathways produced a long-lasting enhancement of the field e.p.s.p. as well as an increased size and a reduced latency of the population spike. This long-lasting potentiation was observed for up to 110 min after tetanization. Extracellular unit recordings showed that this potentiation is accompanied by an increased probability of firing and a reduced firing latency. Intracellular recordings showed an increased e.p.s.p., through the increase was smaller and less regular than for the extracellular field e.p.s.p. 4. No corresponding changes were seen in the field potential responses to stimulation of the untetanized input path, or in the intracellularly measured soma membrane potential, resistance, or excitability. The latter two properties were measured by intracellular injection of current pulses. It is concluded that long-lasting potentiation is specific to the pathway which has received the tetanization. 5. Following tetanization there was also a short-lasting (usually 2-4 min) depression, most often seen for the control pathway but sometimes visible on the tetanized side as well, superimposed on the potentiation. It is concluded that the short-lasting depression is not confined to any particular pathway but is a generalized (unspecific) phenomenon.