Muscarinic depression of long-term potentiation in CA3 hippocampal neurons

Behavioral studies have suggested that muscarinic cholinergic systems have an important role in learning and memory. A muscarinic cholinergic agonist is now shown to affect synaptic plasticity in the CA3 region of the hippocampal slice. Long-term potentiation (LTP) of the mossy fiber-CA3 synapse was blocked by muscarine. Low concentrations of muscarine (1 micromolar) had little effect on low-frequency (0.2 hertz) synaptic stimulation but did significantly reduce the magnitude and probability of induction of LTP. Experiments under voltage clamp showed that muscarine blocked the increase in excitatory synaptic conductance normally associated with LTP at this synapse. These results suggest a possible role for cholinergic systems in synaptic plasticity.     

Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity

Activation of N-methyl-d-aspartate subtype glutamate receptors (NMDARs) is required for long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission at hippocampal CA1 synapses, the proposed cellular substrates of learning and memory. However, little is known about how activation of NMDARs leads to these two opposing forms of synaptic plasticity. Using hippocampal slice preparations, we showed that selectively blocking NMDARs that contain the NR2B subunit abolishes the induction of LTD but not LTP. In contrast, preferential inhibition of NR2A-containing NMDARs prevents the induction of LTP without affecting LTD production. These results demonstrate that distinct NMDAR subunits are critical factors that determine the polarity of synaptic plasticity.     

Postsynaptic calcium is sufficient for potentiation of hippocampal synaptic transmission

Brief repetitive activation of excitatory synapses in the hippocampus leads to an increase in synaptic strength that lasts for many hours. This long-term potentiation (LTP) of synaptic transmission is the most compelling cellular model in the vertebrate brain for learning and memory. The critical role of postsynaptic calcium in triggering LTP has been directly examined using three types of experiment. First, nitr-5, a photolabile nitrobenzhydrol tetracarboxylate calcium chelator, which releases calcium in response to ultraviolet light, was used. Photolysis of nitr-5 injected into hippocampal CA1 pyramidal cells resulted in a large enhancement of synaptic transmission. Second, in agreement with previous results, buffering intracellular calcium at low concentrations blocked LTP. Third, depolarization of the postsynaptic membrane so that calcium entry is suppressed prevented LTP. Taken together, these results demonstrate that an increase in postsynaptic calcium is necessary to induce LTP and sufficient to potentiate synaptic transmission.     

A pertussis toxin-sensitive G protein in hippocampal long-term potentiation

High-frequency (tetanic) stimulation of presynaptic nerve tracts in the hippocampal region of the brain can lead to long-term synaptic potentiation (LTP). Pertussis toxin prevented the development of tetanus-induced LTP in the stratum radiatum-CA1 synaptic system of rat hippocampal slices, indicating that a guanosine triphosphate-binding protein (G protein) may be required for the initiation of LTP. This G protein may be located at a site distinct from the postsynaptic neuron (that is, in presynaptic terminals or glial cells) since maximal activation of CA1 neuronal G proteins by intracellular injection of guanosine-5'-O-(3-thiotriphosphate), a nonhydrolyzable analog of guanosine 5'-triphosphate, did not occlude LTP.     

Transmission between pairs of hippocampal slice neurons: quantal levels, oscillations, and LTP

Long-term potentiation (LTP) of synaptic transmission after coincident pre- and postsynaptic activity is considered a cellular model of changes underlying learning and memory. In intact tissue, LTP has been observed only between populations of neurons, making analysis of mechanisms difficult. Transmission between individual pre- and postsynaptic hippocampal cells was studied, suggesting quantal amplitude distributions with little variability in quantal size. LTP between such pairs is manifested by large, persistent, and synapse-specific potentiation with a shift in amplitude distribution that suggests presynaptic changes. Oscillations in amplitude of transmission, apparently of presynaptic origin, are common and can be triggered by LTP.     

Comparison of two forms of long-term potentiation in single hippocampal neurons

In invertebrate nervous systems, some long-lasting increases in synaptic efficacy result from changes in the presynaptic cell. In the vertebrate nervous system, the best understood long-lasting change in synaptic strength is long-term potentiation (LTP) in the CA1 region of the hippocampus. Here the process is initiated postsynaptically, but the site of the persistent change is unresolved. Single CA3 hippocampal pyramidal cells receive excitatory inputs from associational-commissural fibers and from the mossy fibers of dentate granule cells and both pathways exhibit LTP. Although the induction of associational-commissural LTP requires in the postsynaptic cell N-methyl-D-aspartate (NMDA) receptor activation, membrane depolarization, and a rise in calcium, mossy fiber LTP does not. Paired-pulse facilitation, which is an index of increased transmitter release, is unaltered during associational-commissural LTP but is reduced during mossy fiber LTP. Thus, both the induction and the persistent change may be presynaptic in mossy fiber LTP but not in associational-commissural LTP.     

Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines

Long-term potentiation (LTP) at glutamatergic synapses is considered to underlie learning and memory and is associated with the enlargement of dendritic spines. Because the consolidation of memory and LTP require protein synthesis, it is important to clarify how protein synthesis affects spine enlargement. In rat brain slices, the repetitive pairing of postsynaptic spikes and two-photon uncaging of glutamate at single spines (a spike-timing protocol) produced both immediate and gradual phases of spine enlargement in CA1 pyramidal neurons. The gradual enlargement was strongly dependent on protein synthesis and brain-derived neurotrophic factor (BDNF) action, often associated with spine twitching, and was induced specifically at the spines that were immediately enlarged by the synaptic stimulation. Thus, this spike-timing protocol is an efficient trigger for BDNF secretion and induces protein synthesis-dependent long-term enlargement at the level of single spines.     

Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP

Long-term potentiation (LTP) of synaptic transmission is a widely studied cellular example of synaptic plasticity. However, the identity, localization, and interplay among the biochemical signals underlying LTP remain unclear. Intracellular microelectrodes have been used to record synaptic potentials and deliver protein kinase inhibitors to postsynaptic CA1 pyramidal cells. Induction of LTP is blocked by intracellular delivery of H-7, a general protein kinase inhibitor, or PKC(19-31), a selective protein kinase C (PKC) inhibitor, or CaMKII(273-302), a selective inhibitor of the multifunctional Ca2+-calmodulin-dependent protein kinase (CaMKII). After its establishment, LTP appears unresponsive to postsynaptic H-7, although it remains sensitive to externally applied H-7. Thus both postsynaptic PKC and CaMKII are required for the induction of LTP and a presynaptic protein kinase appears to be necessary for the expression of LTP.     

Storage of spatial information by the maintenance mechanism of LTP

Analogous to learning and memory storage, long-term potentiation (LTP) is divided into induction and maintenance phases. Testing the hypothesis that the mechanism of LTP maintenance stores information requires reversing this mechanism in vivo and finding out whether long-term stored information is lost. This was not previously possible. Recently however, persistent phosphorylation by the atypical protein kinase C isoform, protein kinase Mzeta (PKMz), has been found to maintain late LTP in hippocampal slices. Here we show that a cell-permeable PKMz inhibitor, injected in the rat hippocampus, both reverses LTP maintenance in vivo and produces persistent loss of 1-day-old spatial information. Thus, the mechanism maintaining LTP sustains spatial memory.     

Learning-induced LTP in neocortex

The hypothesis that learning occurs through long-term potentiation (LTP)- and long-term depression (LTD)-like mechanisms is widely held but unproven. This hypothesis makes three assumptions: Synapses are modifiable, they modify with learning, and they strengthen through an LTP-like mechanism. We previously established the ability for synaptic modification and a synaptic strengthening with motor skill learning in horizontal connections of the rat motor cortex (MI). Here we investigated whether learning strengthened these connections through LTP. We demonstrated that synapses in the trained MI were near the ceiling of their modification range, compared with the untrained MI, but the range of synaptic modification was not affected by learning. In the trained MI, LTP was markedly reduced and LTD was enhanced. These results are consistent with the use of LTP to strengthen synapses during learning.     

Long-term potentiation in dentate gyrus: induction by asynchronous volleys in separate afferents

Long-term potentiation (LTP), a long-lasting enhancement of synaptic efficacy, is considered a model for learning and memory. In anesthetized rats, activation of dentate granule cells by stimulating either the medial or lateral perforant pathway at frequencies of 100 to 400 Hz produced LTP of the stimulated pathway preferentially at 400 Hz. However, hippocampal pathways do not normally fire at this high rate. Stimuli at 200 Hz were then applied to either the medial or lateral pathway separately, to both pathways simultaneously, or to the two pathways asynchronously so that the composite stimulus applied to the granule cell dendrite was 400 Hz. LTP was produced preferentially in the asynchronous condition. Thus, lower frequency, physiological input volleys arriving asynchronously at medial and lateral synapses can induce LTP by activating a 400-Hz sensitive mechanism capable of integrating spatially separated granule cell inputs. This may reflect how LTP is normally produced in the dentate gyrus.     

Postsynaptic Induction of BDNF-Mediated Long-Term Potentiation

Brain-derived neurotrophic factor (BDNF) and other neurotrophins are critically involved in long-term potentiation (LTP). Previous reports point to a presynaptic site of neurotrophin action. By imaging dentate granule cells in mouse hippocampal slices, we identified BDNF-evoked Ca2+ transients in dendrites and spines, but not at presynaptic sites. Pairing a weak burst of synaptic stimulation with a brief dendritic BDNF application caused an immediate and robust induction of LTP. LTP induction required activation of postsynaptic Ca2+ channels and N-methyl-d-aspartate receptors and was prevented by the blockage of postsynaptic Ca2+ transients. Thus, our results suggest that BDNF-mediated LTP is induced postsynaptically. Our finding that dendritic spines are the exclusive synaptic sites for rapid BDNF-evoked Ca2+ signaling supports this conclusion.     

Long-term potentiation of neuron-glia synapses mediated by Ca2+-permeable AMPA receptors

Interactions between neurons and glial cells in the brain may serve important functions in the development, maintenance, and plasticity of neural circuits. Fast neuron-glia synaptic transmission has been found between hippocampal neurons and NG2 cells, a distinct population of macroglia-like cells widely distributed in the brain. We report that these neuron-glia synapses undergo activity-dependent modifications analogous to long-term potentiation (LTP) at excitatory synapses, a hallmark of neuronal plasticity. However, unlike the induction of LTP at many neuron-neuron synapses, both induction and expression of LTP at neuron-NG2 synapses involve Ca2+-permeable AMPA receptors on NG2 cells.     

Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction

To elucidate mechanisms that control and execute activity-dependent synaptic plasticity, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPA-Rs) with an electrophysiological tag were expressed in rat hippocampal neurons. Long-term potentiation (LTP) or increased activity of the calcium/calmodulin-dependent protein kinase II (CaMKII) induced delivery of tagged AMPA-Rs into synapses. This effect was not diminished by mutating the CaMKII phosphorylation site on the GluR1 AMPA-R subunit, but was blocked by mutating a predicted PDZ domain interaction site. These results show that LTP and CaMKII activity drive AMPA-Rs to synapses by a mechanism that requires the association between GluR1 and a PDZ domain protein.     

Does BDNF have pre- or postsynaptic targets?

A type of synaptic plasticity in the brain called long-term potentiation (LTP) is thought to form the molecular basis of learning and memory. In a Perspective, Manabe discusses new findings (Kovalchuk et al.) showing brain-derived neurotropic factor modulates LTP by binding to TrkB receptors on the postsynaptic neuron.     

Long-term synaptic potentiation

Long-term synaptic potentiation (LTP) is a leading candidate for a synaptic mechanism of rapid learning in mammals. LTP is a persistent increase in synaptic efficacy that can be quickly induced. The biophysical process that controls one type of LTP is formally similar to a synaptic memory mechanism postulated decades ago by the psychologist Donald Hebb. A key aspect of the modification process involves the N-methyl-D-aspartate (NMDA) receptor-ionophore complex. This ionophore allows calcium influx only if the endogenous ligand glutamate binds to the NMDA receptor and if the voltage across the associated channel is also sufficiently depolarized to relieve a magnesium block. According to one popular hypothesis, the resulting increase in the intracellular calcium concentration activates protein kinases that enhance the postsynaptic conductance. Further biophysical and molecular understanding of the modification process should facilitate detailed explorations of the mnemonic functions of LTP.     

Recycling endosomes supply AMPA receptors for LTP

Long-term potentiation (LTP) of synaptic strength, the most established cellular model of information storage in the brain, is expressed by an increase in the number of postsynaptic AMPA receptors. However, the source of AMPA receptors mobilized during LTP is unknown. We report that AMPA receptors are transported from recycling endosomes to the plasma membrane for LTP. Stimuli that triggered LTP promoted not only AMPA receptor insertion but also generalized recycling of cargo and membrane from endocytic compartments. Thus, recycling endosomes supply AMPA receptors for LTP and provide a mechanistic link between synaptic potentiation and membrane remodeling during synapse modification.     

Frequency-dependent noradrenergic modulation of long-term potentiation in the hippocampus

Norepinephrine, briefly superfused during high-frequency stimulation of the mossy fibers in the rat hippocampal slice in vitro, produced a reversible increase in the magnitude, duration, and probability of induction of long-term synaptic potentiation in the CA3 subfield. Similar results were obtained with isoproterenol, whereas propranolol or timolol reversibly blocked long-term potentiation. Norepinephrine had little apparent effect on responses obtained during low-frequency stimulation of the mossy fibers. These data suggest that norepinephrine can mediate long-lasting, frequency-dependent modulation of synaptic transmission in the mammalian brain. Furthermore, the results suggest a plausible mechanism for some of the known associative interactions between synaptic inputs to hippocampal neurons.     

Anti-Hebbian long-term potentiation in the hippocampal feedback inhibitory circuit

Long-term potentiation (LTP), which approximates Hebb's postulate of associative learning, typically requires depolarization-dependent glutamate receptors of the NMDA (N-methyl-D-aspartate) subtype. However, in some neurons, LTP depends instead on calcium-permeable AMPA-type receptors. This is paradoxical because intracellular polyamines block such receptors during depolarization. We report that LTP at synapses on hippocampal interneurons mediating feedback inhibition is "anti-Hebbian":Itis induced by presynaptic activity but prevented by postsynaptic depolarization. Anti-Hebbian LTP may occur in interneurons that are silent during periods of intense pyramidal cell firing, such as sharp waves, and lead to their altered activation during theta activity.     

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.