Active control of spike-timing dependent synaptic plasticity in an electrosensory system.

A spike timing dependent learning rule is present at the synapse between parallel fibers and Purkinje-like medium ganglion cells in the electrosensory lobe of mormyrid electric fish. The synapse is depressed when a postsynaptic dendritic spike occurs within 50 ms of the onset of a parallel fiber excitatory postsynaptic potential, but is enhanced at all other timing relations. Operation of this learning rule results in the cancellation of predictable membrane potential changes, driving the cell towards a constant output frequency. But medium ganglion cells show a strong and predictable response to corollary discharge signals associated with the motor command that initiates the electric organ discharge. The modeling study presented here resolves this conflict by proposing an active control of dendritic spike threshold during the brief period of medium ganglion cell response.     

Mechanisms and significance of spike-timing dependent plasticity

Hebb's original postulate left two important issues unaddressed: (i) what is the effective time window between pre- and postsynaptic activity that will result in potentiation? and (ii) what is the learning rule that underlies decreases in synaptic strength? While research over the past 2 decades has addressed these questions, several studies within the past 5 years have shown that synapses undergo long-term depression (LTD) or long-term potentiation (LTP) depending on the order of activity in the pre- and postsynaptic cells. This process has been referred to as spike-timing dependent plasticity (STDP). Here we discuss the experimental data on STDP, and develop models of the mechanisms that may underlie it. Specifically, we examine whether the standard model of LTP and LTD in which high and low levels of Ca(2+) produce LTP and LTD, respectively, can also account for STDP. We conclude that the standard model can account for a type of STDP in which, counterintuitively, LTD will be observed at some intervals in which the presynaptic cell fires before the postsynaptic cell. This form of STDP will also be sensitive to parameters such as the presence of an after depolarization following an action potential. Indeed, the sensitivity of this type of STDP to experimental parameters suggests that it may not play an important physiological role in vivo. We suggest that more robust forms of STDP, which do not exhibit LTD at pre-before-post intervals, are not accounted for by the standard model, and are likely to rely on a second coincidence detector in addition to the NMDA receptor.     

Intrinsic stability of temporally shifted spike-timing dependent plasticity

Spike-timing dependent plasticity (STDP), a widespread synaptic modification mechanism, is sensitive to correlations between presynaptic spike trains and it generates competition among synapses. However, STDP has an inherent instability because strong synapses are more likely to be strengthened than weak ones, causing them to grow in strength until some biophysical limit is reached. Through simulations and analytic calculations, we show that a small temporal shift in the STDP window that causes synchronous, or nearly synchronous, pre- and postsynaptic action potentials to induce long-term depression can stabilize synaptic strengths. Shifted STDP also stabilizes the postsynaptic firing rate and can implement both Hebbian and anti-Hebbian forms of competitive synaptic plasticity. Interestingly, the overall level of inhibition determines whether plasticity is Hebbian or anti-Hebbian. Even a random symmetric jitter of a few milliseconds in the STDP window can stabilize synaptic strengths while retaining these features. The same results hold for a shifted version of the more recent "triplet" model of STDP. Our results indicate that the detailed shape of the STDP window function near the transition from depression to potentiation is of the utmost importance in determining the consequences of STDP, suggesting that this region warrants further experimental study.     

钙依赖性突触的可塑性

突触前和突触后细胞内钙离子（[Ca^2 ]i)在短时程和长时程突触的可塑性中,发挥着重要的住处传递作用。兴奋后残留[Ca^2 ]i,可以激发短时程突触增强。突触前[Ca^2 ]i可以影响被抑制的突触前膜囊泡的更新,并准确编码突前和突触后信息,产生截然相反的长时程突触修（ＬＴＰ或ＬＴＤ）。     

Biophysical and phenomenological models of multiple spike interactions in spike-timing dependent plasticity

Spike-timing dependent plasticity (STDP) is a form of associative synaptic modification which depends on the respective timing of pre- and post-synaptic spikes. The biophysical mechanisms underlying this form of plasticity are currently not known. We present here a biophysical model which captures the characteristics of STDP, such as its frequency dependency, and the effects of spike pair or spike triplet interactions. We also make links with other well-known plasticity rules. A simplified phenomenological model is also derived, which should be useful for fast numerical simulation and analytical investigation of the impact of STDP at the network level.     

Hippocampal chromatin‐modifying enzymes are pivotal for scopolamine‐induced synaptic plasticity gene expression changes and memory impairment

The amnesic potential of scopolamine is well manifested through synaptic plasticity gene expression changes and behavioral paradigms of memory impairment. However, the underlying mechanism remains obscure and consequently ideal therapeutic target is lacking. In this context, chromatin‐modifying enzymes, which regulate memory gene expression changes, deserve major attention. Therefore, we analyzed the expression of chromatin‐modifying enzymes and recovery potential of enzyme modulators in scopolamine‐induced amnesia. Scopolamine administration drastically up‐regulated DNA methyltransferases (DNMT1) and HDAC2 expression while CREB‐binding protein (CBP), DNMT3a and DNMT3b remained unaffected. HDAC inhibitor sodium butyrate and DNMT inhibitor Aza‐2′deoxycytidine recovered scopolamine‐impaired hippocampal‐dependent memory consolidation with concomitant increase in the expression of synaptic plasticity genes Brain‐derived neurotrophic factor (BDNF) and Arc and level of histone H3K9 and H3K14 acetylation and decrease in DNA methylation level. Sodium butyrate showed more pronounced effect than Aza‐2′deoxycytidine and their co‐administration did not exhibit synergistic effect on gene expression. Taken together, we showed for the first time that scopolamine‐induced up‐regulation of chromatin‐modifying enzymes, HDAC2 and DNMT1, leads to gene expression changes and consequent decline in memory consolidation. Our findings on the action of scopolamine as an epigenetic modulator can pave a path for ideal therapeutic targets.

     

Kinetic models of spike-timing dependent plasticity and their functional consequences in detecting correlations

Spike-timing dependent plasticity (STDP) is a type of synaptic modification found relatively recently, but the underlying biophysical mechanisms are still unclear. Several models of STDP have been proposed, and differ by their implementation, and in particular how synaptic weights saturate to their minimal and maximal values. We analyze here kinetic models of transmitter-receptor interaction and derive a series of STDP models. In general, such kinetic models predict progressive saturation of the weights. Various forms can be obtained depending on the hypotheses made in the kinetic model, and these include a simple linear dependence on the value of the weight (“soft bounds”), mixed soft and abrupt saturation (“hard bound”), or more complex forms. We analyze in more detail simple soft-bound models of Hebbian and anti-Hebbian STDPs, in which nonlinear spike interactions (triplets) are taken into account. We show that Hebbian STDPs can be used to selectively potentiate synapses that are correlated in time, while anti-Hebbian STDPs depress correlated synapses, despite the presence of nonlinear spike interactions. This correlation detection enables neurons to develop a selectivity to correlated inputs. We also examine different versions of kinetics-based STDP models and compare their sensitivity to correlations. We conclude that kinetic models generally predict soft-bound dynamics, and that such models seem ideal for detecting correlations among large numbers of inputs.     

Tuning bat LSO neurons to interaural intensity differences through spike-timing dependent plasticity

Bats, like other mammals, are known to use interaural intensity differences (IID) to determine azimuthal position. In the lateral superior olive (LSO) neurons have firing behaviors which vary systematically with IID. Those neurons receive excitatory inputs from the ipsilateral ear and inhibitory inputs from the contralateral one. The IID sensitivity of a LSO neuron is thought to be due to delay differences between the signals coming from both ears, differences due to different synaptic delays and to intensity-dependent delays. In this paper we model the auditory pathway until the LSO. We propose a learning scheme where inputs to LSO neurons start out numerous with different relative delays. Spike timing-dependent plasticity (STDP) is then used to prune those connections. We compare the pruned neuron responses with physiological data and analyse the relationship between IID’s of teacher stimuli and IID sensitivities of trained LSO neurons.     

Group I mGluR regulates the polarity of spike-timing dependent plasticity in substantia gelatinosa neurons

The spinal synaptic plasticity is associated with a central sensitization of nociceptive input, which accounts for the generation of hyperalgesia in chronic pain. However, how group I metabotropic glutamate receptors (mGluRs) may operate spinal plasticity remains essentially unexplored. Here, we have identified spike-timing dependent synaptic plasticity in substantia gelatinosa (SG) neurons, using perforated patch-clamp recordings of SG neuron in a spinal cord slice preparation. In the presence of bicuculline and strychnine, long-term potentiation (LTP) was blocked by AP-5 and Ca2+ chelator BAPTA-AM. The group I mGluR antagonist AIDA, PLC inhibitor U-73122, and IP3 receptor blocker 2-APB shifted LTP to long-term depression (LTD) without affecting acute synaptic transmission. These findings provide a link between postsynaptic group I mGluR/PLC/IP3-gated Ca2+ store regulating the polarity of synaptic plasticity and spinal central sensitization.     

Mitogen-activated protein kinases in synaptic plasticity and memory

This review highlights five areas of recent discovery concerning the role of extracellular-signal regulated kinases (ERKs) in the hippocampus. First, ERKs have recently been directly implicated in human learning through studies of a human mental retardation syndrome. Second, new models are being formulated for how ERKs contribute to molecular information processing in dendrites. Third, a role of ERKs in stabilizing structural changes in dendritic spines has been defined. Fourth, a crucial role for ERKs in regulating local dendritic protein synthesis is emerging. Fifth, the importance of ERK interactions with scaffolding and structural proteins at the synapse is increasingly apparent. These topics are discussed within the context of an emerging role for ERKs in a wide variety of forms of synaptic plasticity and memory formation in the behaving animal.     

Molecular mechanisms of synaptic plasticity and memory.

To unravel the molecular and cellular bases of learning and memory is one of the most ambitious goals of modern science. The progress of recent years has not only brought us closer to understanding the molecular mechanisms underlying stable, long-lasting changes in synaptic strength, but it has also provided further evidence that these mechanisms are required for memory formation.     

Protein kinase signaling in synaptic plasticity and memory

The relay of extracellular signals into changes in cellular physiology involves a Byzantine array of intracellular signaling pathways, of which cytoplasmic protein kinases are a crucial component. In the nervous system, a great deal of effort has focused on understanding the conversion of patterns of synaptic activity into long-lasting changes in synaptic efficacy that are thought to underlie memory. The goal is both to understand synaptic plasticity mechanisms, such as long-term potentiation, at a molecular level and to understand the relationship of these synaptic mechanisms to behavioral memory. Although both involve the activation of multiple signaling pathways, recent studies are beginning to define discrete roles and mechanisms for individual kinases in the different temporal phases of both synaptic and behavioral plasticity.     

Spike timing dependent synaptic plasticity in biological systems

 Association of a presynaptic spike with a postsynaptic spike can lead to changes in synaptic efficacy that are highly dependent on the relative timing of the pre- and postsynaptic spikes. Different synapses show varying forms of such spike-timing dependent learning rules. This review describes these different rules, the cellular mechanisms that may be responsible for them, and the computational consequences of these rules for information processing and storage in the nervous system. Received: 16 January 2002 / Accepted: 3 June 2002 Acknowledgements. This research is supported in part by a National Science Foundation grant IBN 98-08887 (awarded to PDR), and by National Institutes of Health grants R01-MH49792 (awarded to CCB), R01-MH60996 (awarded to CCB), and R01-MH60996 (awarded to PDR). Correspondence to: P. D. Roberts (e-mail: robertpa@ohsu.edu)     

Spike-timing dependent synaptic plasticity: a phenomenological framework

 In this paper a phenomenological model of spike-timing dependent synaptic plasticity (STDP) is developed that is based on a Volterra series-like expansion. Synaptic weight changes as a function of the relative timing of pre- and postsynaptic spikes are described by integral kernels that can easily be inferred from experimental data. The resulting weight dynamics can be stated in terms of statistical properties of pre- and postsynaptic spike trains. Generalizations to neurons that fire two different types of action potentials, such as cerebellar Purkinje cells where synaptic plasticity depends on correlations in two distinct presynaptic fibers, are discussed. We show that synaptic plasticity, together with strictly local bounds for the weights, can result in synaptic competition that is required for any form of pattern formation. This is illustrated by a concrete example where a single neuron equipped with STDP can selectively strengthen those synapses with presynaptic neurons that reliably deliver precisely timed spikes at the expense of other synapses which transmit spikes with a broad temporal distribution. Such a mechanism may be of vital importance for any neuronal system where information is coded in the timing of individual action potentials. Received: 23 January 2002 / Accepted: 28 March 2002 Correspondence to: W.M. Kistler (e-mail: kistler@anat.fgg.eur.nl Fax: +31 10 408 5459)     

Age‐related changes in hippocampal‐dependent synaptic plasticity and memory mediated by p75 neurotrophin receptor

The plasticity mechanisms in the nervous system that are important for learning and memory are greatly impacted during aging. Notably, hippocampal‐dependent long‐term plasticity and its associative plasticity, such as synaptic tagging and capture (STC), show considerable age‐related decline. The p75 neurotrophin receptor (p75^NTR) is a negative regulator of structural and functional plasticity in the brain and thus represents a potential candidate to mediate age‐related alterations. However, the mechanisms by which p75^NTR affects synaptic plasticity of aged neuronal networks and ultimately contribute to deficits in cognitive function have not been well characterized. Here, we report that mutant mice lacking the p75^NTR were resistant to age‐associated changes in long‐term plasticity, associative plasticity, and associative memory. Our study shows that p75^NTR is responsible for age‐dependent disruption of hippocampal homeostatic plasticity by modulating several signaling pathways, including BDNF, MAPK, Arc, and RhoA‐ROCK2‐LIMK1‐cofilin. p75^NTR may thus represent an important therapeutic target for limiting the age‐related memory and cognitive function deficits.     

Dendritic protein synthesis, synaptic plasticity, and memory

Considerable evidence suggests that the formation of long-term memories requires a critical period of new protein synthesis. Recently, the notion that some of these newly synthesized proteins originate through local translation in neuronal dendrites has gained some traction. Here, we review the experimental support for this idea and highlight some of the key questions outstanding in this area.