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John E Lisman

Publications and source records attributed to John E Lisman.

17 recordsLinked to original sources
PubMed2006

Testing the role of calmodulin in the excitation of Limulus photoreceptors.

The phototransduction cascade in Limulus ventral photoreceptors involves multiple second messengers, including Ca(2+) and cGMP. Light-induced Ca(2+) release from intracellular stores is an intermediate step, but the subsequent Ca(2+)-activated reaction remains to be determined. The possibility that Ca(2+)/calmodulin (Ca(2+)/CaM) might be involved is suggested by the high calmodulin content of the transducing lobe. To test whether CaM can excite the transduction cascade we injected a 25 microM Ca(2+)/CaM solution. This produced a rapid, brief depolarization similar to that produced by light, suggesting a role for CaM in the cascade. However, an important caveat is that Ca(2+) dissociating from the Ca(2+)/CaM complex might excite this process. Several control experiments argue against, but do not entirely eliminate this possibility. To test whether endogenous CaM has a function in excitation, trifluoperazine was pressure injected into the rhabdomeric region. The response to brief flashes was not affected, but the response to steady illumination was transiently attenuated by each injection. We conclude that calmodulin should be considered a candidate to couple intermediate and late stages of the transduction cascade.

Animals↗
PubMed2006

Role of the neurogranin concentrated in spines in the induction of long-term potentiation.

Synaptic plasticity in CA1 hippocampal neurons depends on Ca2+ elevation and the resulting activation of calmodulin-dependent enzymes. Induction of long-term depression (LTD) depends on calcineurin, whereas long-term potentiation (LTP) depends on Ca2+/calmodulin-dependent protein kinase II (CaMKII). The concentration of calmodulin in neurons is considerably less than the total concentration of the apocalmodulin-binding proteins neurogranin and GAP-43, resulting in a low level of free calmodulin in the resting state. Neurogranin is highly concentrated in dendritic spines. To elucidate the role of neurogranin in synaptic plasticity, we constructed a computational model with emphasis on the interaction of calmodulin with neurogranin, calcineurin, and CaMKII. The model shows how the Ca2+ transients that occur during LTD or LTP induction affect calmodulin and how the resulting activation of calcineurin and CaMKII affects AMPA receptor-mediated transmission. In the model, knockout of neurogranin strongly diminishes the LTP induced by a single 100 Hz, 1 s tetanus and slightly enhances LTD, in accord with experimental data. Our simulations show that exchange of calmodulin between a spine and its parent dendrite is limited. Therefore, inducing LTP with a short tetanus requires calmodulin stored in spines in the form of rapidly dissociating calmodulin-neurogranin complexes.

Calcium↗
PubMed2005

Recall of memory sequences by interaction of the dentate and CA3: a revised model of the phase precession.

Behavioral and electrophysiological evidence indicates that the hippocampus has a special role in the encoding and recall of memory sequences. Importantly, the hippocampal phase precession, a phenomenon recorded as a rat moves through place fields, can be interpreted as cued recall of the sequence of upcoming places. The phase precession can be recorded in all hippocampal regions, but the role of each region has been unclear. Here, we suggest how the dentate and CA3 regions can work together to learn sequences, recall sequences, and generate the phase precession. Our proposal is constrained by information regarding synaptic plasticity rules, network connectivity, timing delays and theta/gamma oscillations.

Animals↗
PubMed2005

The hippocampal-VTA loop: controlling the entry of information into long-term memory.

In this article we develop the concept that the hippocampus and the midbrain dopaminergic neurons of the ventral tegmental area (VTA) form a functional loop. Activation of the loop begins when the hippocampus detects newly arrived information that is not already stored in its long-term memory. The resulting novelty signal is conveyed through the subiculum, accumbens, and ventral pallidum to the VTA where it contributes (along with salience and goal information) to the novelty-dependent firing of these cells. In the upward arm of the loop, dopamine (DA) is released within the hippocampus; this produces an enhancement of LTP and learning. These findings support a model whereby the hippocampal-VTA loop regulates the entry of information into long-term memory.

Animals↗
PubMed2005

Inhibition of perforant path input to the CA1 region by serotonin and noradrenaline.

Bath-applied monoamines-dopamine (DA), serotonin (5-HT), and noradrenaline (NE)-strongly suppress the perforant path (PP) input to CA1 hippocampal region with very little effect on the Schaffer collaterals (SC) input. The effect of DA action on PP field excitatory postsynaptic potential (fEPSP) has been characterized in detail, but relatively little is known about the NE and 5-HT effects. Here we show that the maximal inhibition of the PP fEPSP by NE is approximately 55%, whereas 5-HT inhibition is weaker ( approximately 35%). The half-maximal inhibitory concentration of both 5-HT and NE is approximately 1 muM. Neither NE nor 5-HT affected paired-pulse facilitation, suggesting that the effect is not presynaptic. This is in contrast to DA, which does have a presynaptic effect. The NE effect was blocked by alpha2 antagonists, whereas the alpha1 antagonist corynanthine and beta-antagonist propranolol were ineffective. The effect of 5-HT was mimicked by the agonist, 5-carboxamidotryptamine maleate (5-CT), and not affected by adrenergic and dopaminergic antagonists. To determine the 5-HT receptors involved, we tested a number of 5-HT antagonists, but none produced a complete suppression of the 5-HT effect. Of these, only the 5-HT7 and 5-HT2 antagonists produced weak but significant inhibition of 5-HT effect. We conclude that NE inhibits the PP fEPSP through postsynaptic action on alpha2-adrenoceptors and that 5-HT7, 5-HT2, and some other receptor may be involved in 5-HT action in PP.

Adrenergic alpha-Antagonists↗
PubMed2005

The stability of a stochastic CaMKII switch: dependence on the number of enzyme molecules and protein turnover.

Molecular switches have been implicated in the storage of information in biological systems. For small structures such as synapses, these switches are composed of only a few molecules and stochastic fluctuations are therefore of importance. Such fluctuations could potentially lead to spontaneous switch reset that would limit the lifetime of information storage. We have analyzed a model of the calcium/calmodulin-dependent protein kinase II (CaMKII) switch implicated in long-term memory in the nervous system. The bistability of this switch arises from autocatalytic autophosphorylation of CaMKII, a reaction that is countered by a saturable phosphatase-1-mediated dephosphorylation. We sought to understand the factors that control switch stability and to determine the functional relationship between stability and the number of molecules involved. Using Monte Carlo simulations, we found that the lifetime of states of the switch increase exponentially with the number of CaMKII holoenzymes. Switch stability requires a balance between the kinase and phosphatase rates, and the kinase rate must remain high relative to the rate of protein turnover. Thus, a critical limit on switch stability is set by the observed turnover rate (one per 30 h on average). Our computational results show that, depending on the timescale of fluctuations in enzyme numbers, for a switch composed of about 15 CaMKII holoenzymes, the stable persistent activation can span from a few years to a human lifetime.

Calcium-Calmodulin-Dependent Protein Kinase Type 2↗
PubMed2005

Hippocampal sequence-encoding driven by a cortical multi-item working memory buffer.

Encoding and recall of memory sequences is an important process. Memory encoding is thought to occur by long-term potentiation (LTP) in the hippocampus; however, it remains unclear how LTP, which has a time window for induction of approximately 100 ms, could encode the linkage between sequential items that arrive with a temporal separation >100 ms. Here, we argue that LTP can underlie the learning of such memory sequences, provided the input to the hippocampus is from a cortical multi-item working memory buffer in which theta and gamma oscillations have an important role. In such a buffer, memory items that occurred seconds apart are represented with a temporal separation of 20-30 ms, thereby bringing them within the LTP window. The physiological and behavioral evidence for such a buffer will be reviewed.

Animals↗
PubMed2004

Contribution of Ih and GABAB to synaptically induced afterhyperpolarizations in CA1: a brake on the NMDA response.

CA1 pyramidal cells receive two major excitatory inputs: the perforant path (PP) terminates in the most distal dendrites, whereas the Schaffer collaterals (SC) terminate more proximally. We have examined the mechanism of the afterhyperpolarization (AHP) that follows single subthreshold excitatory postsynaptic potentials (EPSPs) in these inputs. The AHPs were not reduced by a GABAA antagonist or by agents that block Ca2+ entry. Application of the Ih blocker, ZD7288, partially blocked the AHP in the PP; the substantial remaining component was blocked by 2-hydroxysaclofen, a GABAB antagonist. In contrast, the AHP in the SC depends nearly completely on Ih, with almost no GABAB component. Thus postsynaptic GABAB receptors appear to be preferentially involved at distal synapses, consistent with the spatial distribution of GABAB receptors and g protein-coupled inward rectifying potassium (GIRK) channels. GABAB does, however, play a role at proximal synapses through presynaptic suppression of glutamate release, a mechanism that is much weaker at distal synapses. Experiments were conducted to explore the functional role of the AHP in the PP, which has a higher N-methyl-D-aspartate (NMDA)/AMPA ratio than the SC. Blockade of the AHP converted a response that had a small NMDA component to one that had a large component. These results indicate that the Ih and postsynaptic GABAB conductances act as a brake on distally generated NMDA responses.

Animals↗
PubMed2004

Properties of quantal transmission at CA1 synapses.

We have used Monte Carlo simulations to understand the generation of quantal responses at the single active zones of CA1 synapses. We constructed a model of AMPA channel activation that accounts for the responses to controlled glutamate application and a model of glutamate diffusion in the synaptic cleft. With no further adjustments to these models, we simulated the response to the release of glutamate from a single vesicle. The predicted response closely matches the rise time of observed responses, which recent measurements show is much faster (<100 micros) than previously thought. The simulations show that initial channel opening is driven by a brief (<100 micros) glutamate spike near the site of vesicle fusion, producing a hotspot of channel activation (diameter: approximately 250 nm) smaller than many synapses. Quantal size therefore depends more strongly on the density of channels than their number, a finding that has important implications for measuring synaptic strength. Recent measurements allow estimation of AMPA receptor density at CA1 synapses. Using this value, our simulations correctly predicts a quantal amplitude of approximately 10 pA. We have also analyzed the properties of excitatory postsynaptic currents (EPSCs) generated by the multivesicular release that can occur during evoked responses. We find that summation is nearly linear and that the existence of multiple narrow peaks in amplitude histograms can be accounted for. It has been unclear how to reconcile the existence of these narrow peaks, which indicate that the variation of quantal amplitude is small (CV < 0.2) with the highly variable amplitude of miniature EPSCs (mEPSCs; CV approximately 0.6). According to one theory, mEPSC variability arises from variation in vesicle glutamate content. However, both our modeling results and recent experimental results indicate that this view cannot account for the observed rise time/amplitude correlation of mEPSCs. In contrast, this correlation and the high mEPSC variability can be accounted for if some mEPSCs are generated by two or more vesicles released with small temporal jitter. We conclude that a broad range of results can be accounted for by simple principles: quantal amplitude (approximately 10 pA) is stereotyped, some mEPSCs are multivesicular at moderate and large synapses, and evoked responses are generated by quasi-linear summation of multiple quanta.

Benzothiadiazines↗
PubMed2004

The excitation cascade of Limulus ventral photoreceptors: guanylate cyclase as the link between InsP3-mediated Ca2+ release and the opening of cGMP-gated channels.

BACKGROUND: Early stages in the excitation cascade of Limulus photoreceptors are mediated by activation of Gq by rhodopsin, generation of inositol-1,4,5-trisphosphate by phospholipase-C and the release of Ca2+. At the end of the cascade, cGMP-gated channels open and generate the depolarizing receptor potential. A major unresolved issue is the intermediate process by which Ca2+ elevation leads to channel opening. RESULTS: To explore the role of guanylate cyclase (GC) as a potential intermediate, we used the GC inhibitor guanosine 5'-tetraphosphate (GtetP). Its specificity in vivo was supported by its ability to reduce the depolarization produced by the phosphodiesterase inhibitor IBMX. To determine if GC acts subsequent to InsP3 production in the cascade, we examined the effect of intracellular injection of GtetP on the excitation caused by InsP3 injection. This form of excitation and the response to light were both greatly reduced by GtetP, and they recovered in parallel. Similarly, GtetP reduced the excitation caused by intracellular injection of Ca2+. In contrast, this GC inhibitor did not affect the excitation produced by injection of a cGMP analog. CONCLUSION: We conclude that GC is downstream of InsP3-induced Ca2+ release and is the final enzymatic step of the excitation cascade. This is the first invertebrate rhabdomeric photoreceptor for which transduction can be traced from rhodopsin photoisomerization to ion channel opening.

Animals↗
PubMed2003

Distribution of postsynaptic density (PSD)-95 and Ca2+/calmodulin-dependent protein kinase II at the PSD.

Postsynaptic densities (PSDs) contain proteins that regulate synaptic transmission. We determined the positions of calcium/calmodulin-dependent protein kinase II (CaMKII) and PSD-95 within the three-dimensional structure of isolated PSDs using immunogold labeling, rotary shadowing, and electron microscopic tomography. The results show that all PSDs contain a central mesh immediately underlying the postsynaptic membrane. Label for PSD-95 is found on both the cytoplasmic and cleft sides of this mesh, averaging 12 nm from the cleft side. All PSDs label for PSD-95. The properties of CaMKII labeling are quite different. Label is virtually absent on the cleft sides of PSDs, but can be heavy on the cytoplasmic side at a mean distance of 25 nm from the cleft. In tomograms, CaMKII holoenzymes can be visualized directly, appearing as labeled, tower-like structures reflecting the 20 nm diameter of the holoenzyme. These towers protrude from the cytoplasmic side of the central mesh. There appears to be a local organization of CaMKII, as judged by fact that the nearest-neighbor distances are nearly invariant over a wide range of labeling density for CaMKII. The average density of CaMKII holoenzymes is highly variable, ranging from zero to values approaching a tightly packed state. This variability is significantly higher than that for PSD-95 and is consistent with an information storage role for CaMKII.

Animals↗
PubMed2002

Pathway-specific properties of AMPA and NMDA-mediated transmission in CA1 hippocampal pyramidal cells.

CA1 pyramidal cells receive glutamatergic input from the entorhinal cortex through the perforant path (PP) and from CA3 through Schaffer collaterals (SC). The PP input terminates in the stratum lacunosum molecular approximately 300 microm from the cell body, whereas SC synapses have a more proximal location in the stratum radiatum. We compared the properties of AMPA- and NMDA-mediated transmission at these two inputs. The AMPA-mediated components have linear voltage dependence in both inputs. The reversal potential in the PP is only slightly more positive than in the SC, indicating that distal membrane voltage could be effectively set. The NMDA-mediated responses in the two pathways, however, are very different. The PP exhibits inward rectification, as evidenced by very low outward currents. The rectification persists in the absence of extracellular Mg2+. It cannot be attributed to clamping problems, because large outward AMPA currents can be observed even when conditions are modified to have the AMPA currents kinetically match the NMDA currents. Thus, it appears that the PP NMDA channels have novel properties. A second difference between the PP and SC pathways is that the PP has a larger NMDA/AMPA charge ratio. This difference could be observed under many conditions, including block of all voltage-dependent conductances and elimination of the negative resistance of NMDA channels by removing extracellular Mg2+. The difference in ratio thus cannot be attributed to regenerative currents. The higher NMDA component of the distal PP synapses could help to make these synapses more powerful under depolarizing conditions.

Animals↗
PubMed2002

Simultaneous roles for Ca2+ in excitation and adaptation of Limulus ventral photoreceptors.

The ventral photoreceptors of Limulus have been one of the main preparations for the study of invertebrate phototransduction. The study of ventral photoreceptors has revealed that they have remarkable performance characteristics, most notably the very large amplification of the transduction process. This amplification is critically dependent upon the coupling of photoactivated rhodopsin to the phosphoinositide cascade, resulting in the release of Ca2+ from intracellular stores. The consequent elevation of Ca2+ within the photoreceptor's cytosol is amongst the most rapid and dramatic known to be activated by the phosphoinositide cascade. This review summarizes the evidence that intracellular Ca2+ is a key regulator of transduction in Limulus photoreceptors. The mechanisms that regulate Ca2+ as well as the possible targets of the action of Ca2+ are reviewed. Ca2+ elevation is critical for triggering both excitation and adaptation processes in the photoreceptor. The question of how a single second messenger can produce these two opposing effects is of obvious interest and is a topic dealt with throughout this review.

Animals↗
PubMed2002

Model for a robust neural integrator.

Integrator circuits in the brain show persistent firing that reflects the sum of previous excitatory and inhibitory inputs from external sources. Integrator circuits have been implicated in parametric working memory, decision making and motor control. Previous work has shown that stable integrator function can be achieved by an excitatory recurrent neural circuit, provided synaptic strengths are tuned with extreme precision (better than 1% accuracy). Here we show that integrator circuits can function without fine tuning if the neuronal units have bistable properties. Two specific mechanisms of bistability are analyzed, one based on local recurrent excitation, and the other on the voltage-dependence of the NMDA (N-methyl-D-aspartate) channel. Neither circuit requires fine tuning to perform robust integration, and the latter actually exploits the variability of neuronal conductances.

Computer Simulation↗
PubMed2002

Oscillations in the alpha band (9-12 Hz) increase with memory load during retention in a short-term memory task.

To study the role of brain oscillations in working memory, we recorded the scalp electroencephalogram (EEG) during the retention interval of a modified Sternberg task. A power spectral analysis of the EEG during the retention interval revealed a clear peak at 9-12 Hz, a frequency in the alpha band (8-13 Hz). In apparent conflict with previous ideas according to which alpha band oscillations represent brain "idling", we found that the alpha peak systematically increased with the number of items held in working memory. The enhancement was prominent over the posterior and bilateral central regions. The enhancement over posterior regions is most likely explained by the well known alpha rhythm produced close to the parietal-occipital fissure, whereas the lateral enhancement could be explained by sources in somato-motor cortex. A time-frequency analysis revealed that the enhancement was present throughout the last 2.5 s of the 2.8 s retention interval and that alpha power rapidly diminished following the probe. The load dependence and the tight temporal regulation of alpha provide strong evidence that the alpha generating system is directly or indirectly linked to the circuits responsible for working memory. Although a clear peak in the theta band (5-8 Hz) was only detectable in one subject, other lines of evidence indicate that theta occurs and also has a role in working memory. Hypotheses concerning the role of alpha band activity in working memory are discussed.

Adolescent↗
PubMed2002

Postsynaptic application of a cAMP analogue reverses long-term potentiation in hippocampal CA1 pyramidal neurons.

The molecular mechanisms that underlie the maintenance of long-term potentiation (LTP) remain unclear. We have examined the influence of postsynaptic cAMP-dependent processes on LTP maintenance in CA1 hippocampal cells. After LTP induction, drugs affecting cAMP-dependent processes were perfused into the cell through a patch pipette. A cAMP analogue, Rp-cAMPS (4 mM), dramatically decreased the amplitude of potentiated synaptic responses. The amplitude of responses in the control pathway was also decreased but to a lesser extent, indicating a specific effect on the potentiation process. This specific effect was not due to the larger amplitude of potentiated responses, was not use-dependent and, unlike other factors that affect LTP maintenance, did not depend on the delay (2, 10, or 25 min) of drug application after LTP induction. Lower concentrations of Rp-cAMPS (1.0 and 0.4 mM) also produced an inhibitory effect but reduced the LTP and control pathways comparably. One possible action of Rp-cAMPS is competitive inhibition of protein kinase A (PKA). Surprisingly, a potent and noncompetitive PKA inhibitor, regulatory type II subunit of PKA, produced only a weak depression of potentiated and control responses indicating there must be other targets for Rp-cAMPS. Moreover, Sp-8-OH-cAMPS, which is an activator of PKA, and Rp-8-OH-cAMPS, which is a weak inhibitor of PKA, both produced effects similar to those of Rp-cAMPS. We conclude that there are postsynaptic cyclic nucleotide-dependent processes that can specifically alter the mechanisms that maintain LTP and that are not primarily dependent on PKA.

Animals↗