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John Lisman

Publications and source records attributed to John Lisman.

14 recordsLinked to original sources
PubMed2006

A unified model of the presynaptic and postsynaptic changes during LTP at CA1 synapses.

Long-term potentiation (LTP) has been studied extensively at CA1 synapses of the hippocampus, and there is evidence implicating both postsynaptic and presynaptic changes in this process. These changes include (i) addition of AMPA channels to the extrasynaptic membrane and diffusional equilibrium of extrasynaptic receptors with synaptic receptors, (ii) sudden addition of AMPA channels to the synapse in large groups, (iii) a change in the mode of glutamate release (presumably from kiss-and-run to full fusion), and (iv) a delayed increase in the number of vesicles released. However, it remains unclear whether (or how) these changes work together. We have incorporated all of these processes into a structural model of the synapse. We propose that the synapse is composed of transsynaptic modules that function quasi-independently in AMPA-mediated transmission. Under basal conditions, synapses are partially silent; some modules are AMPA-silent (but contribute to NMDA-mediated transmission), whereas others are functional (and contribute to both AMPA- and NMDA-mediated transmission). During LTP, there is both a rapid change in the mode of vesicle fusion and a rapid insertion of a postsynaptic complex (a hyperslot) containing many proteins (slots) capable of binding AMPA channels. The combined effect of these pre- and postsynaptic changes is to convert AMPA-silent modules into functional modules. Slot filling is transiently enhanced by a rapid increase in extrasynaptic GluR1, a form of the AMPA-type receptor. A slower transsynaptic growth process adds AMPA-silent modules to the synapse, enhancing the number of vesicles released and thereby enhancing the NMDA response. This model accounts for a broad range of data, including the LTP-induced changes in quantal parameters. The model also provides a coherent explanation for the diverse effects of GluR1 knockout on basal transmission, LTP, and distance-dependent scaling.

Animals↗
PubMed2005

The theta/gamma discrete phase code occuring during the hippocampal phase precession may be a more general brain coding scheme.

In the hippocampus, oscillations in the theta and gamma frequency range occur together and interact in several ways, indicating that they are part of a common functional system. It is argued that these oscillations form a coding scheme that is used in the hippocampus to organize the readout from long-term memory of the discrete sequence of upcoming places, as cued by current position. This readout of place cells has been analyzed in several ways. First, plots of the theta phase of spikes vs. position on a track show a systematic progression of phase as rats run through a place field. This is termed the phase precession. Second, two cells with nearby place fields have a systematic difference in phase, as indicated by a cross-correlation having a peak with a temporal offset that is a significant fraction of a theta cycle. Third, several different decoding algorithms demonstrate the information content of theta phase in predicting the animal's position. It appears that small phase differences corresponding to jitter within a gamma cycle do not carry information. This evidence, together with the finding that principle cells fire preferentially at a given gamma phase, supports the concept of theta/gamma coding: a given place is encoded by the spatial pattern of neurons that fire in a given gamma cycle (the exact timing within a gamma cycle being unimportant); sequential places are encoded in sequential gamma subcycles of the theta cycle (i.e., with different discrete theta phase). It appears that this general form of coding is not restricted to readout of information from long-term memory in the hippocampus because similar patterns of theta/gamma oscillations have been observed in multiple brain regions, including regions involved in working memory and sensory integration. It is suggested that dual oscillations serve a general function: the encoding of multiple units of information (items) in a way that preserves their serial order. The relationship of such coding to that proposed by Singer and von der Malsburg is discussed; in their scheme, theta is not considered. It is argued that what theta provides is the absolute phase reference needed for encoding order. Theta/gamma coding therefore bears some relationship to the concept of "word" in digital computers, with word length corresponding to the number of gamma cycles within a theta cycle, and discrete phase corresponding to the ordered "place" within a word.

Action Potentials↗
PubMed2005

Postsynaptic depolarization requirements for LTP and LTD: a critique of spike timing-dependent plasticity.

Long-term potentiation and long-term depression require postsynaptic depolarization, which many current models attribute to backpropagating action potentials. New experimental work suggests, however, that other mechanisms can lead to dendritic depolarization, and that backpropagating action potentials may be neither necessary nor sufficient for synaptic plasticity in vivo.

Action Potentials↗
PubMed2004

Persistent accumulation of calcium/calmodulin-dependent protein kinase II in dendritic spines after induction of NMDA receptor-dependent chemical long-term potentiation.

Calcium/calmodulin-dependent protein kinase II (CaMKII) is a leading candidate for a synaptic memory molecule because it is persistently activated after long-term potentiation (LTP) induction and because mutations that block this persistent activity prevent LTP and learning. Previous work showed that synaptic stimulation causes a rapidly reversible translocation of CaMKII to the synaptic region. We have now measured green fluorescent protein (GFP)-CaMKIIalpha translocation into synaptic spines during NMDA receptor-dependent chemical LTP (cLTP) and find that under these conditions, translocation is persistent. Using red fluorescent protein as a cell morphology marker, we found that there are two components of the persistent accumulation. cLTP produces a persistent increase in spine volume, and some of the increase in GFP-CaMKIIalpha is secondary to this volume change. In addition, cLTP results in a dramatic increase in the bound fraction of GFP-CaMKIIalpha in spines. To further study the bound pool, immunogold electron microscopy was used to measure CaMKIIalpha in the postsynaptic density (PSD), an important regulator of synaptic function. cLTP produced a persistent increase in the PSD-associated pool of CaMKIIalpha. These results are consistent with the hypothesis that CaMKIIalpha accumulation at synapses is a memory trace of past synaptic activity.

Adenylyl Cyclases↗
PubMed2003

Forskolin-induced LTP in the CA1 hippocampal region is NMDA receptor dependent.

Chemically induced long-term potentiation (cLTP) could potentially work by directly stimulating the biochemical machinery that underlies synaptic plasticity, bypassing the need for synaptic activation. Previous reports suggested that agents that raise cAMP concentration might have this capability. We examined the cLTP induced in acute slices by application of Sp-cAMPS or a combination of the adenylyl cyclase activator, forskolin, and the phosphodiesterase inhibitor, rolipram. Under our conditions, cLTP was induced but only if inhibition was reduced. We found that this form of cLTP was blocked by a N-methyl-d-aspartate receptor (NMDAR) antagonist and required the low-frequency test stimulation typically used to monitor the strength of synapses. Interestingly, similar LTP could be induced by lowering the Mg(2+) concentration of the ACSF during forskolin/rolipram or Sp-cAMPS application or even by just lowering Mg(2+) concentration alone. This LTP was also NMDAR dependent and required only a few ( approximately 5) low-frequency stimuli for its induction. The finding that even low-frequency synaptic stimulation was sufficient for LTP induction indicates that a highly sensitized plasticity state was generated. The fact that some stimulation was required means that potentiation is probably restricted to the stimulated axons, limiting the usefulness of this form of cLTP. However, when similar experiments were conducted using slice cultures, potentiation occurred without test stimuli, probably because the CA3-CA1 connections are extensive and because presynaptic spontaneous activity is sufficient to fulfill the activity requirement. As in acute slices, the potentiation was blocked by an NMDAR antagonist. Our general conclusion is that the induction of LTP caused by elevating cAMP requires presynaptic activity and NMDA channel opening. The method of inducing cLTP in slice cultures will be useful when it is desirable to produce NMDAR-dependent LTP in a large fraction of synapses.

Animals↗
PubMed2003

Actin's actions in LTP-induced synapse growth.

F-actin is required for LTP induction, but the underlying mechanisms are unclear. New results show that LTP produces an increase in actin-rich spines. Furthermore, these spines have large synapses, strongly suggesting that LTP involves synapse growth. This process appears to require LIMK-1 phosphorylation of the actin depolymerizing factor cofilin.

Actins↗
PubMed2003

Long-term potentiation: outstanding questions and attempted synthesis.

This article attempts an overview of the mechanism of NMDAR-dependent long-term potentiation (LTP) and its role in hippocampal networks. Efforts are made to integrate information, often in speculative ways, and to identify unresolved issues about the induction, expression and molecular storage processes. The pre/post debate about LTP expression has been particularly difficult to resolve. The following hypothesis attempts to reconcile the available physiological evidence as well as anatomical evidence that LTP increases synapse size. It is proposed that synapses are composed of a variable number of trans-synaptic modules, each having presynaptic release sites and a postsynaptic structure that can be AMPAfied by the addition of a hyperslot assembly that anchors 10-20 AMPA channels. According to a newly developed view of transmission, the quantal response is generated by AMPA channels near the site of vesicle release and so will depend on whether the module where release occurs has been AMPAfied. LTP expression may involve two structurally mediated processes: (i) the AMPAfication of existing modules by addition of hyperslot assemblies: this is a purely postsynaptic process and produces an increase in the probability of an AMPA response, with no change in the NMDA component; and (ii) the addition of new modules: this is a structurally coordinated pre/post process that leads to LTP-induced synapse enlargement and potentiation of the NMDA component owing to an increase in the number of release sites (the number of NMDA channels is assumed to be fixed). The protocol used for LTP induction appears to affect the proportion of these two processes; pairing protocols that involve low-frequency presynaptic stimulation induce only AMPAfication, making LTP purely postsynaptic, whereas high-frequency stimulation evokes both processes, giving rise to a presynaptic component. This model is capable of reconciling much of the seemingly contradictory evidence in the pre/post debate. The structural nature of the postulated changes is relevant to a second debate: whether a CaMKII switch or protein-dependent structural change is the molecular memory mechanism. A possible reconciliation is that a reversible CaMKII switch controls the construction of modules and hyperslot assemblies from newly synthesized proteins.

Animals↗
PubMed2003

Recognition by top-down and bottom-up processing in cortex: the control of selective attention.

Visual recognition is achieved by a hierarchy of bidirectionally connected cortical areas. The entry of signals into higher areas involves the serial sampling of information within a movable window of attention. Here we explore how the cortex can move this window and integrate the sampled information. To make this concrete, we modeled the process of visual word recognition by hierarchical cortical areas representing features, letters, and words. At the start of the recognition process, nodes representing all contextually possible words are active. Simple connectivity rules allow a parallel top-down (T-D) computation of the relative probability of each feature at each location given the set of active words. This information is then used to guide the window of attention to information-rich features (e.g., a feature that is present in the visual image but has lowest probability). Bottom-up processing of this feature excludes words that do not contain it and leads to T-D recomputation of feature probabilities. Recognition occurs after several such cycles when all but one word has been excluded. We show that when 950 words are stored in long-term memory, recognition occurs after an average of 4.9 cycles. Because covert attention can be moved every 20-30 ms, word recognition could be as fast as determined experimentally (<200 ms of cortical processing). This model accounts for the findings that recognition time depends logarithmically on set size, recognition time is reduced when context reduces the number of possible targets, the time to classify a nonword decreases when its approximation to English decreases, and in high level cortex, the firing of neurons tuned to an object increases progressively as its recognition occurs. More generally the model provides a physiologically plausible view of how bi-directional signal flow in cortex guides attention to produce efficient recognition.

Animals↗
PubMed2003

The high variance of AMPA receptor- and NMDA receptor-mediated responses at single hippocampal synapses: evidence for multiquantal release.

Most of our knowledge about transmission at central synapses has been obtained by studying populations of synapses, but some important properties of synapses can be determined only by studying them individually. An important issue is whether a presynaptic action potential causes, at most, a single vesicle to be released, or whether multiquantal transmission is possible. Previous work in the CA1 region has shown that the response to stimulation of a single axon can be highly variable, apparently because it is composed of a variable number of quantal elements ( approximately 5 pA in amplitude). These quantal events have a low coefficient of variation (CV). Because the number of synaptic contacts involved is not known, the response could be because of uniquantal transmission at a varying number of synapses, or to multliquantal transmission at a single synapse. The former predicts that the CV at individual synapses should be small. We have used optical methods to measure the N-methyl-D-aspartate receptor-mediated Ca(2+) elevation at single active synapses. Our main finding is that the amplitude of nonfailure responses could be highly variable, having a CV as large as 0.63. In one fortuitous experiment, the optically studied synapse was the only active synapse, and we could therefore measure both its N-methyl-D-aspartate (NMDA) receptor- and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated signals. At this synapse, both signals varied over a 10-fold range and were highly correlated. These results strongly suggest that transmission at single CA1 synapses can be multiquantal. Furthermore, the individual quantal response is very far from saturation, allowing the effective summation of many quanta. The existence of multiquantal release has important implications for defining synaptic strength and understanding the mechanisms of synaptic plasticity.

Animals↗
PubMed2003

Gamma oscillations correlate with working memory load in humans.

Functional imaging of human cortex implicates a diverse network of brain regions supporting working memory - the capacity to hold and manipulate information for short periods of time. Although we are beginning to map out the brain networks supporting working memory, little is known about its physiological basis. We analyzed intracranial recordings from two epileptic patients as they performed a working memory task. Spectral analyses revealed that, in both patients, gamma (30-60 Hz) oscillations increased approximately linearly with memory load, tracking closely with memory load over the course of the trial. This constitutes the first evidence that gamma oscillations, widely implicated in perceptual processes, support the maintenance of multiple items in working memory.

Brain Mapping↗
PubMed2003

Information encoding and computation with spikes and bursts.

Neurons compute and communicate by transforming synaptic input patterns into output spike trains. The nature of this transformation depends crucially on the properties of voltage-gated conductances in neuronal membranes. These intrinsic membrane conductances can enable neurons to generate different spike patterns including brief, high-frequency bursts that are commonly observed in a variety of brain regions. Here we examine how the membrane conductances that generate bursts affect neural computation and encoding. We simulated a bursting neuron model driven by random current input signal and superposed noise. We consider two issues: the timing reliability of different spike patterns and the computation performed by the neuron. Statistical analysis of the simulated spike trains shows that the timing of bursts is much more precise than the timing of single spikes. Furthermore, the number of spikes per burst is highly robust to noise. Next we considered the computation performed by the neuron: how different features of the input current are mapped into specific output spike patterns. Dimensional reduction and statistical classification techniques were used to determine the stimulus features triggering different firing patterns. Our main result is that spikes, and bursts of different durations, code for different stimulus features, which can be quantified without a priori assumptions about those features. These findings lead us to propose that the biophysical mechanisms of spike generation enables individual neurons to encode different stimulus features into distinct spike patterns.

Computer Simulation↗
PubMed2002

Bursting neurons signal input slope.

Brief bursts of high-frequency action potentials represent a common firing mode of pyramidal neurons, and there are indications that they represent a special neural code. It is therefore of interest to determine whether there are particular spatial and temporal features of neuronal inputs that trigger bursts. Recent work on pyramidal cells indicates that bursts can be initiated by a specific spatial arrangement of inputs in which there is coincident proximal and distal dendritic excitation (Larkum et al., 1999). Here we have used a computational model of an important class of bursting neurons to investigate whether there are special temporal features of inputs that trigger bursts. We find that when a model pyramidal neuron receives sinusoidally or randomly varying inputs, bursts occur preferentially on the positive slope of the input signal. We further find that the number of spikes per burst can signal the magnitude of the slope in a graded manner. We show how these computations can be understood in terms of the biophysical mechanism of burst generation. There are several examples in the literature suggesting that bursts indeed occur preferentially on positive slopes (Guido et al., 1992; Gabbiani et al., 1996). Our results suggest that this selectivity could be a simple consequence of the biophysics of burst generation. Our observations also raise the possibility that neurons use a burst duration code useful for rapid information transmission. This possibility could be further examined experimentally by looking for correlations between burst duration and stimulus variables.

Action Potentials↗
PubMed2002

A large sustained Ca2+ elevation occurs in unstimulated spines during the LTP pairing protocol but does not change synaptic strength.

Synapses in the CA1 region of the hippocampus undergo bidirectional synaptic modification in response to different patterns of activity. Postsynaptic Ca2+ elevation can trigger either synaptic strengthening or weakening, depending on the properties of the local Ca2+ signal. During the pairing protocol for long-term potentiation (LTP) induction, the cell is depolarized under voltage-clamp and is given low-frequency synaptic stimulation. As an initial step toward understanding the Ca2+ dynamics during this process, we used confocal microscopy to study the Ca2+ signals in spines evoked by the depolarization itself. This depolarization activates voltage-dependent Ca2+ channels (VDCC), but whether these channels inactivate rapidly or remain functional throughout the long depolarizations used in the pairing protocol remains unknown. Cells were depolarized to 0 mV for 2-3 min. This depolarization led to a large initial elevation of Ca2+ in spines that never decayed back to resting levels. The maintained signal was close to the Kd of the low-affinity (5 microM) Ca2+ dye, Magnesium Green. We attempted to determine the functional role of this elevation, using the Ca2+-channel blocker D-890. The addition of D-890 in the internal solution produced a nearly complete abolition of the Ca2+ elevation during depolarization. Under these conditions, the NMDA conductance was normal, but LTP was almost completely blocked. This might suggest the importance of VDCC in LTP; however, we found that high concentrations of D-890 can directly inhibit calmodulin protein kinase II (CaMKII), an enzyme required for LTP induction. Thus, whereas D-890 is a useful tool for blocking postsynaptic VDCC, it cannot be used to study the contribution of these channels to plasticity. We conclude that the activation of VDCC produces a large and persistent elevation of Ca2+ in all spines, but does not produce either LTP or long-term depression (LTD) in the absence of synaptic stimulation. The possible reasons for this are discussed.

Animals↗