Mechanisms Of Long-term Potentiation Induction Research Articles

Механізми довготривалої потенціації в нейронах гіпокампа

Long-term potentiation is involved in the mechanisms of synaptic plasticity, provides such processes as memory and learning, and allows the nervous system of a living organism to adapt to changing environmental conditions. It is an increase in the efficiency of glutamatergic synapses, which lasts much longer than other types of potentiation in the nervous system. Despite the fact that long-term potentiation has been studied in detail, the physiological mechanisms of its formation, which lead to an increase of synaptic weight, remain incompletely understood. Well known that long-term potentiation is closely dependent on the processes of rapid axonal transport. However, how axonal transport is related to the mechanisms of long-term potentiation induction and expression, what substances are transported through axons, and how they affect the synaptic activity of postsynaptic neurons is currently unknown. We review here the main physiological mechanisms that occur in the neurons of the hippocampus and contribute to the formation of long-term potentiation. The works of recent years devoted to the study of the participation of synaptic tagging, retrograde signaling, morphological modifications and axonal transport in formation of the long-term potentiation are analyzed.

Synaptic plasticity and spatial working memory are impaired in the CD mouse model of Williams-Beuren syndrome.

Mice heterozygous for a complete deletion (CD) equivalent to the most common deletion found in individuals with Williams-Beuren syndrome (WBS) recapitulate relevant features of the neurocognitive phenotype, such as hypersociability, along with some neuroanatomical alterations in specific brain areas. However, the pathophysiological mechanisms underlying these phenotypes still remain largely unknown. We have studied the synaptic function and cognition in CD mice using hippocampal slices and a behavioral test sensitive to hippocampal function. We have found that long-term potentiation (LTP) elicited by theta burst stimulation (TBS) was significantly impaired in hippocampal field CA1 of CD animals. This deficit might be associated with the observed alterations in spatial working memory. However, we did not detect changes in presynaptic function, LTP induction mechanisms or AMPA and NMDA receptor function. Reduced levels of Brain-derived neurotrophic factor (BDNF) were present in the CA1-CA3 hippocampal region of CD mice, which could account for LTP deficits in these mice. Taken together, these results suggest a defect of CA1 synapses in CD mice to sustain synaptic strength after stimulation. These data represent the first description of synaptic functional deficits in CD mice and further highlights the utility of the CD model to study the mechanisms underlying the WBS neurocognitive profile.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0258-7) contains supplementary material, which is available to authorized users.

Ethanol inhibits long-term potentiation in hippocampal CA1 neurons, irrespective of lamina and stimulus strength, through neurosteroidogenesis.

Ethanol inhibits memory encoding and the induction of long-term potentiation (LTP) in CA1 neurons of the hippocampus. Hippocampal LTP at Schaffer collateral synapses onto CA1 pyramidal neurons has been widely studied as a cellular model of learning and memory, but there is striking heterogeneity in the underlying molecular mechanisms in distinct regions and in response to distinct stimuli. Basal and apical dendrites differ in terms of innervation, input specificity, and molecular mechanisms of LTP induction and maintenance, and different stimuli determine distinct molecular pathways of potentiation. However, lamina or stimulus-dependent effects of ethanol on LTP have not been investigated. Here, we tested the effect of acute application of 60 mM ethanol on LTP induction in distinct dendritic compartments (apical versus basal) of CA1 neurons, and in response to distinct stimulation paradigms (single versus repeated, spaced high frequency stimulation). We found that ethanol completely blocks LTP in apical dendrites, whereas it reduces the magnitude of LTP in basal dendrites. Acute ethanol treatment for just 15 min altered pre- and post-synaptic protein expression. Interestingly, ethanol increases the neurosteroid allopregnanolone, which causes ethanol-dependent inhibition of LTP, more prominently in apical dendrites, where ethanol has greater effects on LTP. This suggests that ethanol has general effects on fundamental properties of synaptic plasticity, but the magnitude of its effect on LTP differs depending on hippocampal sub-region and stimulus strength.

Endogenous opioid peptides contribute to associative LTP in the hippocampal CA3 region

The medial and lateral perforant path projections to the hippocampal CA3 region display distinct mechanisms of long-term potentiation (LTP) induction, N-methyl-d-aspartate (NMDA) and opioid receptor dependent, respectively. However, medial and lateral perforant path projections to the CA3 region display associative LTP with coactivation, suggesting that while they differ in receptors involved in LTP induction they may share common downstream mechanisms of LTP induction. Here we address this interaction of LTP induction mechanisms by evaluating the contribution of opioid receptors to the induction of associative LTP among the medial and lateral perforant path projections to the CA3 region in vivo. Local application of the opioid receptor antagonists naloxone or Cys2-Tyr3-Orn5-Pen7-amide (CTOP) normally block induction of lateral perforant path-CA3 LTP. However, these opioid receptor antagonists failed to block associative LTP in lateral perforant path-CA3 synapses when it was induced by strong coactivation of the medial perforant pathway which displays NMDAR-dependent LTP. Thus strong activation of non-opioidergic afferents can substitute for the opioid receptor activation required for lateral perforant path LTP induction. Conversely, medial perforant path-CA3 associative LTP was blocked by opioid receptor antagonists when induced by strong coactivation of the opioidergic lateral perforant path. These data indicate endogenous opioid peptides contribute to associative LTP at coactive synapses when induced by strong coactivation of an opioidergic afferent system. These data further suggest that associative LTP induction is regulated by the receptor mechanisms of the strongly stimulated pathway. Thus, while medial and lateral perforant path synapses differ in their mechanisms of LTP induction, associative LTP at these synapses share common downstream mechanisms of induction.

Intact Long-Term Potentiation but Reduced Connectivity between Neocortical Layer 5 Pyramidal Neurons in a Mouse Model of Rett Syndrome

Mutations in MECP2 cause Rett syndrome and some related forms of mental retardation and autism. Mecp2-null mice exhibit symptoms reminiscent of Rett syndrome including deficits in learning. Previous reports demonstrated impaired long-term potentiation (LTP) in slices of symptomatic Mecp2-null mice, and decreased excitatory neurotransmission, but the causal relationship between these phenomena is unclear. Reduced plasticity could lead to altered transmission, or reduced excitatory transmission could alter the ability to induce LTP. To help distinguish these possibilities, we compared LTP induction and baseline synaptic transmission at synapses between layer 5 cortical pyramidal neurons in slices of wild-type and Mecp2-null mice. Paired recordings reveal that LTP induction mechanisms are intact in Mecp2-null connections, even after the onset of symptoms. However, fewer connections were found in Mecp2-null mice and individual connections were weaker. These data suggest that loss of MeCP2 function reduces excitatory synaptic connectivity and that this precedes deficits in plasticity.

The Back and Forth of Dendritic Plasticity

Synapses are located throughout the often-elaborate dendritic tree of central neurons. Hebbian models of plasticity require temporal association between synaptic input and neuronal output to produce long-term potentiation of excitatory transmission. Recent studies have highlighted how active dendritic spiking mechanisms control this association. Here, we review new work showing that associative synaptic plasticity can be generated without neuronal output and that the interplay between neuronal architecture and the active electrical properties of the dendritic tree regulates synaptic plasticity.

Heterosynaptic Facilitation of In Vivo Thalamocortical Long-Term Potentiation in the Adult Rat Visual Cortex by Acetylcholine

Acetylcholine (ACh) plays a permissive role in developmental plasticity of fibers from the lateral geniculate nucleus (LGN) to the primary visual cortex (V1). These fibers remain plastic and express long-term potentiation (LTP) in adult rodents, but it is not known if ACh modulates this form of plasticity in the mature V1. We show that, in anesthetized rats, theta burst stimulation (TBS) of the LGN using 5 or 40 theta cycles produced moderate (approximately 20%) and stronger (approximately 40%) potentiation, respectively, of field postsynaptic potentials recorded in the ipsilateral V1. Basal forebrain stimulation (100 Hz) 5 min after TBS enhanced LTP induced by both weak (5 theta cycles) and strong (40 theta cycles) induction protocols. Both effects were reduced by systemic administration of the muscarinic receptor antagonist scopolamine. Basal forebrain stimulation did not enhance LTP when applied 30 min after or 5 min prior to TBS, suggesting that ACh affects early LTP induction mechanisms. Application of the cholinergic agonist carbachol in V1 by means of reverse microdialysis mimicked the effect of basal forebrain stimulation. We conclude that heterosynaptic facilitation of V1 plasticity by ACh extends beyond early postnatal maturation periods and acts to convert weak potentiation into pronounced, long-lasting increases in synaptic strength.

Active zones for presynaptic plasticity in the brain

Some of the most abundant synapses in the brain such as the synapses formed by the hippocampal mossy fibers, cerebellar parallel fibers and several types of cortical afferents express presynaptic forms of long-term potentiation (LTP), a putative cellular model for spatial, motor and fear learning. Those synapses often display presynaptic mechanisms of LTP induction, which are either NMDA receptor independent of dependent of presynaptic NMDA receptors. Recent investigations on the molecular mechanisms of neurotransmitter release modulation in short- and long-term synaptic plasticity in central synapses give a preponderant role to active zone proteins as Munc-13 and RIM1-alpha, and point toward the maturation process of synaptic vesicles prior to Ca(2+)-dependent fusion as a key regulatory step of presynaptic plasticity.

Non-apoptotic functions of caspase-3 in nervous tissue.

Some enzymes that have been recognized as "apoptotic" so far may be involved in important cellular processes not necessarily related to cell death in nervous tissue. The activity of caspase-3, an "apoptotic" enzyme, can be measured in normally functioning neurons. The results reported by several groups point to the possibility that caspases may be involved in nervous tissue function as top enzymes in the regulatory proteolytic cascade. A concept on a new mechanism of synaptic plasticity modulation involving caspase-3 has been formulated postulating a specific role of caspase-3 in normal brain functioning. The idea of synaptic plasticity modulation by caspase-3 is in line with data reported recently. For example, caspase-3 is possibly involved in the long-term potentiation (LTP) phenomenon since proteins that are key players of molecular mechanisms of LTP induction and maintenance are caspase-3 substrates. Experimental results on blocking LTP by a caspase-3 inhibitor confirm this concept.

Mu opiates inhibit long-term potentiation induction in the spinal cord slice.

Long-term potentiation (LTP) involves a prolonged increase in neuronal excitability following repeated afferent input. This phenomenon has been extensively studied in the hippocampus as a model of learning and memory. Similar long-term increases in neuronal responses have been reported in the dorsal horn of the spinal cord following intense primary afferent stimulation. In these studies, we utilized the spinal cord slice preparation to examine effects of the potently antinociceptive mu opioids in modulating primary afferent/dorsal horn neurotransmission as well as LTP of such transmission. Transverse slices were made from the lumbar spinal cord of 10- to 17-day-old rats, placed in a recording chamber, and perfused with artificial cerebrospinal fluid also containing bicuculline (10 microM) and strychnine (1 microM). Primary afferent activation was achieved in the spinal slice by electrical stimulation of the dorsal root (DR) or the tract of Lissauer (LT) which is known to contain a high percentage of small diameter fibers likely to transmit nociception. Consistent with this anatomy, response latencies of LT-evoked field potentials in the dorsal horn were considerably slower than the response latencies of DR-evoked potentials. Only LT-evoked field potentials were found to be reliably inhibited by the mu opioid receptor agonist [D-Ala(2), N-Me-Phe(4), Gly(5)] enkephalin-ol (DAMGO, 1 microM), although evoked potentials from both DR and LT were blocked by the AMPA/kainate glutamate receptor antagonist 6-cyano-7-nitroquinoxalene-2,3-dione. Moreover repeated stimulation of LT produced LTP of LT- but not DR-evoked potentials. In contrast, repeated stimulation of DR showed no reliable LTP. LTP of LT-evoked potentials depended on N-methyl-D-aspartate (NMDA) receptor activity, in that it was attenuated by the NMDA antagonist APV. Moreover, such LTP was inhibited by DAMGO interfering with LTP induction mechanisms. Finally, in whole cell voltage-clamp studies of Lamina I neurons, DAMGO inhibited excitatory postsynaptic current (EPSC) response amplitudes from LT stimulation-evoked excitatory amino acid release but not from glutamate puffed onto the cell and increased paired-pulse facilitation of EPSCs evoked by LT stimulation. These studies suggest that mu opioids exert their inhibitory effects presynaptically, likely through the inhibition of glutamate release from primary afferent terminals, and thereby inhibit the induction of LTP in the spinal dorsal horn.

Protein tyrosine kinase is required for the induction of long-term potentiation in the rat hippocampus.

1. Protein tyrosine phosphorylation is thought to play an important role in the regulation of neuronal function. Previous work has shown that protein tyrosine kinase (PTK) inhibitors can inhibit the induction of long-term potentiation (LTP), a candidate synaptic mechanism involved in memory formation. However, how PTK activity might contribute to LTP induction remains elusive. To understand the role of PTK pathways in the development of LTP better, a set of studies was implemented in area CA1 of rat hippocampal slices using both intra- and extracellular recordings. We show here that bath application or injection into postsynaptic cells of the PTK inhibitors genistein and lavendustin A blocked the induction of LTP produced by high-frequency tetanic stimulation. 2. Application of lavendustin A 10 min before or 3 min after induction effectively blocked LTP. However, application at 10 or 30 min after induction had no detectable effect on potentiation. 3. PTK inhibitor pretreatment did not affect the long-lasting enhancement of synaptic response produced by phorbol 12,13-dibutyrate (PDBu), forskolin plus 3-isobutyl-L-methylxanthine (IBMX), or tetraethylammonium (TEA). In contrast, PTK inhibitors significantly blocked postanoxic LTP. 4. EPQ(pY)EEIPIA, an activator of Src family PTKs, produced a gradual and robust increase in the synaptic response and occluded LTP. 5. These results suggest that Src family kinases are potential candidates for the PTKs contributing to the molecular mechanism of LTP induction at Schaffer collateral-CA1 synapses.

Toward a molecular explanation for long-term potentiation.

Introduction The molecular mechanisms for long-term potentiation (LTP) may seem hopelessly complex, and no doubt the lack of clarity and concision of the immense LTP literature is a source of frustration for many (Sanes and Lichtman 1999). However, being inherently optimistic it seems to me that certain generalizations are beginning to emerge that allow an initial formulation of a molecular explanation for LTP. At this point in time we do not have in hand all the puzzle pieces concerning the molecular basis for LTP, so any explanation is by necessity incomplete and likely to contain some errors. Nevertheless, I feel it is constructive to present a working draft of a molecular model for one specific type of LTP, in the hope that it will present a useful framework for further discussion and experimentation. In this commentary I will describe several criteria that I use to narrow down the enormous LTP literature, and define certain terms commonly used and misused in the LTP literature so that we have a common vocabulary. I propose a set of criteria for inclusion of a given signal transduction cascade into a “core” mechanism for LTP and present an initial model of such a mechanism for one type of LTP. Finally, I will comment on the complexity of the molecular mechanisms of LTP induction, maintenance, and expression and point out a few emerging themes for the biochemistry of LTP. The latter serves to help manage the complexity of LTP biochemistry by generating functional categories for the molecules of LTP.

Selective scarcity of NMDA receptor channel subunits in the stratum lucidum (mossy fibre-recipient layer) of the mouse hippocampal CA3 subfield.

Hippocampal synapses express two distinct forms of the long-term potentiation (LTP), i.e. NMDA receptor-dependent and -independent LTPs. To understand its molecular-anatomical basis, we produced affinity-purified antibodies against the GluRepsilon1 (NR2A), GluRepsilon2 (NR2B), and GluRzeta1 (NR1) subunits of the N-methyl-D-aspartate (NMDA) receptor channel, and determined their distributions in the mouse hippocampus. Using NMDA receptor subunit-deficient mice as the specificity controls, section pretreatment with proteases (pepsin and proteinase K) was found to be very effective to detect authentic NMDA receptor subunits. As the result of modified immunohistochemistry, all three subunits were detected at the highest level in the strata oriens and radiatum of the CA1 subfield, and high levels were also seen in most other neuropil layers of the CA1 and CA3 subfields and of the dentate gyrus. However, the stratum lucidum, a mossy fibre-recipient layer of the CA3 subfield, contained low levels of the GluRepsilon1 and GluRzeta1 subunits and almost excluded the GluRepsilon2 subunit. Double immunofluorescence with the AMPA receptor GluRalpha1 (GluR1 or GluR-A) subunit further demonstrated that the GluRepsilon1 subunit was colocalized in a subset, not all, of GluRalpha1-immunopositive structures in the stratum lucidum. Therefore, the selective scarcity of these NMDA receptor subunits in the stratum lucidum suggests that a different synaptic targeting mechanism exerts within a single CA3 pyramidal neurone in vivo, which would explain contrasting significance of the NMDA receptor channel in LTP induction mechanisms between the mossy fibre-CA3 synapse and other hippocampal synapses.

Rescuing impairment of long-term potentiation in fyn-deficient mice by introducing Fyn transgene.

To examine the physiological role of the Fyn tyrosine kinase in neurons, we generated transgenic mice that expressed a fyn cDNA under the control of the calcium/calmodulin-dependent protein kinase IIalpha promoter. With this promoter, we detected only low expression of Fyn in the neonatal brain. In contrast, there was strong expression of the fyn-transgene in neurons of the adult forebrain. To determine whether the impairment of long-term potentiation (LTP) observed in adult fyn-deficient mice was caused directly by the lack of Fyn in adult hippocampal neurons or indirectly by an impairment in neuronal development, we generated fyn-rescue mice by introducing the wild-type fyn-transgene into mice carrying a targeted deletion in the endogenous fyn gene. In fyn-rescue mice, Schaffer collateral LTP was restored, even though the morphological abnormalities characteristic of fyn-deficient mice were still present. These results suggest that Fyn contributes, at least in part, to the molecular mechanisms of LTP induction.

Chronic developmental lead exposure increases the threshold for long-term potentiation in rat dentate gyrus in vivo

Chronic developmental lead (Ph) exposure has been long associated with cognitive dysfunction in children and animals. In an attempt to more directly relate the behavioral observations of impaired cognitive ability to Pb-induced effects on neuronal activity, we utilized the long-term potentiation (LTP) model of neural plasticity to assess synaptic function. Male rats were chronically exposed to 0.2% Pb 2+-acetate through the drinking water of the pregnant dam, and directly through their own water supply at weaning. As adults, field potentials evoked by perforant path stimulation were recorded in the dentate gyrus under urethane anesthesia. LTP threshold was determined by applying a series of stimulus trains of increasing intensities. Baseline testing of dentate gyrus field potentials indicated that input/output functions, maximal response amplitudes, and threshold currents required to evoke a population spike (PS) did not differ for control and Pb-exposed animals. Despite similarities in baseline synaptic transmission, Pb-exposed animals required a higher train intensity to evoke LTP than controls. With maximal train stimulation, however, control and Pb animals exhibited comparable levels of potentiation. These findings suggest that the mechanisms of LTP induction are preferentially impaired by Pb exposure. Although baseline synaptic transmission was not altered in Pb-exposed animals, decreases in glutamate release following high K + perfusion and reductions in paired pulse facilitation have been reported in the intact animal. Pb-induced reductions in calcium influx through voltage-sensitive or N-methyl- d-aspartate (NMDA) receptor-dependent channels may mediate increases in LTP threshold. It is possible that the threshold changes in the induction of LTP reported here contribute to cognitive impairments associated with Pb exposure.

Properties of LTP induction in the CA3 region of the primate hippocampus.

Activity-dependent changes in synaptic strength, such as long-term potentiation (LTP), have been proposed to underlie memory storage in the brains of all mammals, including humans. However, most forms of synaptic plasticity, including LTP, are studied almost exclusively in rodents and related species. Thus, the hypothesis that LTP is important in human memory relies on the assumption that LTP is similar in the primate and rodent brains. We have begun to test this hypothesis by studying the properties and mechanisms of LTP induction in area CA3 of hippocampal slices from cynomolgus monkeys. We have found that LTP can be induced reliably at both mossy fiber-CA3 and collateral/associational-CA3 synapses in the primate brain, and that the properties of LTP induction at these synapses are similar to what we and others have observed in experiments using hippocampal slices from rodents. Also, we have investigated the role of opioids in mossy fiber synaptic transmission and LTP and have found no effect of the opioid antagonist naloxone nor the opioid agonist dynorphin on mossy fiber synaptic transmission or potentiation. These data suggest that LTP in the primate and rat brains has a similar induction mechanism and, thus, that the rodent is a useful animal model in which to study synaptic modification such as LTP.

Basal and apical synapses of CA1 pyramidal cells employ different LTP induction mechanisms.

Nitric oxide (NO) production has been widely reported to be required for the induction of long-term potentiation (LTP) in hippocampal CA1 cells. Of the two constitutive isoforms of NO synthase, the endothelial form (eNOS) has been implicated in the induction of LTP in these cells. The distribution of eNOS within CA1 cells is not uniform, however, being present in the cell bodies and apical dendrites but absent from the basal dendrites. Using extracellular and intracellular recording techniques, we demonstrate that LTP induction in stratum radiatum synapses (onto apical dendrites) is dependent on NO production, being attenuated by pretreatment with a NOS inhibitor. LTP induced in stratum oriens synapses (onto basal dendrites) is, however, resistant to NOS inhibitors. Both forms of LTP require the activation of N-methyl-D-aspartate (NMDA) receptors because induction of LTP in both stratum radiatum and stratum oriens is blocked by AP5. Thus, it appears that synapses onto apical and basal dendrites of CA1 cells use different cellular mechanisms of LTP induction.

Functional integrity of NMDA-dependent LTP induction mechanisms across the lifespan of F-344 rats.

Previous studies have reported a lack of an age effect in the induction of long-term potentiation (LTP) at CA1 synapses, using robust (supramaximal) stimulation parameters, but an apparent age effect on the induction threshold of LTP using less robust stimulation, in the perithreshold region. These findings have led to the suggestion that old animals may experience an alteration either in the efficacy of activation of N-methyl-D-aspartate (NMDA) receptors or in the metabolic processes subsequent to NMDA receptor activation that lead to LTP expression. An alternative explanation for the apparent threshold change in old animals is that, because of the known reduction of the intracellularly recorded, compound EPSP magnitude in old rats, equivalent electrical stimulation results in a smaller effective depolarization of the postsynaptic cells and a consequently less effective activation of NMDA receptors, which are otherwise functionally normal. To distinguish between these two hypotheses, weak orthodromic stimulation was paired with intracellularly applied current pulses, thus holding constant the degree of postsynaptic depolarization. No differences in LTP induction threshold or magnitude were observed in a large sample of rats from three age groups. It is concluded that the NMDA receptor mechanisms and associated biochemical processes leading to LTP induction are not altered in aged F-344 rats. The reduced compound EPSP in old animals was reconfirmed in the present study, and a significant correlation was found in old rats between the magnitude of the EPSP at a fixed stimulus level and their performance on a spatial memory task.

Thapsigargin blocks long-term potentiation induced by weak, but not strong tetanisation in rat hippocampal CA1 neurons

To elucidate the role of calcium release from internal stores during different paradigms of tetanisation in long-term potentiation (LTP), we have investigated the effects of thapsigargin on the elevation of the excitatory postsynaptic field potential (fEPSP) and the population spike (PS) after tetanisation. We found no effect on the duration of fEPSP potentiation if thapsigargin was perfused before strong (triple) tetanisation. However, the potentiation was reduced significantly from control experiments if thapsigargin was applied before weak (single) tetanisation. Surprisingly, we did not find any reduction of PS potentiation, which could be due to changes in the recurrent inhibition. We conclude that the involvement of internal calcium release in the mechanisms of LTP induction will be reduced if multiple tetanisation is used.

Neurophysiological analysis of long-term potentiation in mammalian brain

Long-term potentiation (LTP) is a persistent increase in postsynaptic response following a high-frequency presynaptic activation. Characteristic LTP features, including input specificity and associativity, make it a popular model to study memory mechanisms. Mechanisms of LTP induction and maintenance are briefly reviewed. Increased intracellular Ca 2+ concentration is shown to be critical for LTP induction. This increase is believed to be based on Ca 2+ influx secondary to activation of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. Existence of other sources of Ca 2+ increase and other critical factors is now becoming evident. They include voltage-dependent Ca 2+ channels, Ca 2+ intracellular stores, metabotropic glutamate receptors, ‘modulatory’ transmitters. An example of an involvement of voltage-dependent Ca 2+ channels is potentiation induced by intracellular depolarizing pulses. LTP can be divided into decremental earlier (E-LTP) and non-decremental late (L-LTP) phases which explains some inconsistencies in studies of LTP mechanisms. E-LTP is suggested to be based on a transient increase in presynaptic release probabilities. A hypothesis is considered which explains L-LTP by suggesting that Ca 2+ activates structural changes leading to an increase in the synaptic gap resistance. This enhances positive synaptic electrical feedback and augments release probability. The hypothesis predicts specific morphological changes, synchronous transmitter release of two or several quanta in some central synapses and the amplification of such synchronization following LTP induction. Data are discussed which maintain these predictions.