Input-specific Long-term Potentiation Research Articles

Long-term potentiation of the nucleus reuniens and entorhinal cortex to CA1 distal dendritic synapses in mice.

The present study investigated the short-term and long-term synaptic plasticity of excitatory synapses formed by the nucleus reuniens (RE) and entorhinal cortex (EC) on the distal apical dendrites of CA1 pyramidal cells. RE-CA1 synapses are implicated in memory involving the hippocampus and medial prefrontal cortex. Current source density (CSD) analysis was used to identify excitatory and inhibitory currents following stimulation of RE or medial perforant path (MPP) in urethane-anesthetized mice in vivo. At the distal apical dendrites, RE evoked an initial excitatory sink followed by inhibitory sources at short (~ 30ms) and long (150-200ms) latencies, and often showing gamma (25-40Hz) oscillations. Both RE-evoked and spontaneous gamma-frequency local field potentials displayed the same CSD depth profile. Paired-pulse facilitation (PPF) of the distal excitatory sink at 20-200ms interpulse intervals was observed following RE stimulation, generally higher than that following MPP stimulation. Theta-frequency burst stimulation (TBS) of RE induced input-specific long-term potentiation (LTP) at the distal dendritic CA1 synapses, accompanied by reduction of PPF. After TBS of the MPP, the MPP-CA1 distal dendritic synapse could manifest LTP or long-term depression, but the non-tetanized RE-CA1 synapse was typically potentiated. Heterosynaptic potentiation of the RE to CA1 distal synapses may occur after repeated activity of EC afferents, or spread of MPP stimulus currents to coursing RE afferents. The results indicate a propensity of RE-CA1 distal excitatory synapses to show PPF, LTP and gamma oscillations, all of which may participate in memory processing by RE and EC.

Input-Specific NMDAR-Dependent Potentiation of Dendritic GABAergic Inhibition

Preservation of a balance between synaptic excitation and inhibition is critical for normal brain function. A number of homeostatic cellular mechanisms have been suggested to play a role in maintaining this balance, including long-term plasticity of GABAergic inhibitory synapses. Many previous studies have demonstrated a coupling of postsynaptic spiking with modification of perisomatic inhibition. Here, we demonstrate that activation of NMDA-type glutamate receptors leads to input-specific long-term potentiation of dendritic inhibition mediated by somatostatin-expressing interneurons. This form of plasticity is expressed postsynaptically and requires both CaMKIIα and the β2 subunit of the GABA-A receptor. Importantly, this process may function to preserve dendritic inhibition, as genetic deletion of NMDAR signaling results in a selective weakening of dendritic inhibition. Overall, our results reveal a new mechanism for linking excitatory and inhibitory input in neuronal dendrites and provide novel insight into the homeostatic regulation of synaptic transmission in cortical circuits.

Encoding of Discriminative Fear Memory by Input-Specific LTP in the Amygdala

In auditory fear conditioning, experimental subjects learn to associate an auditory conditioned stimulus (CS) with an aversive unconditioned stimulus. With sufficient training, animals fear conditioned to an auditory CS show fear response to the CS, but not to irrelevant auditory stimuli. Although long-term potentiation (LTP) in the lateral amygdala (LA) plays an essential role in auditory fear conditioning, it is unknown whether LTP is induced selectively in theneural pathways conveying specific CS information to the LA in discriminative fear learning. Here, we show that postsynaptically expressed LTP is induced selectively in the CS-specific auditory pathways to the LA in a mouse model of auditory discriminative fear conditioning. Moreover, optogenetically induced depotentiation of the CS-specific auditory pathways to the LA suppressed conditioned fear responses to the CS. Our results suggest that input-specific LTP in the LA contributes to fear memory specificity, enabling adaptive fear responses only to the relevant sensory cue. VIDEO ABSTRACT.

Associative spike timing-dependent potentiation of the basal dendritic excitatory synapses in the hippocampus in vivo

Spike timing-dependent plasticity in the hippocampus has rarely been studied in vivo. Using extracellular potential and current source density analysis in urethane-anesthetized adult rats, we studied synaptic plasticity at the basal dendritic excitatory synapse in CA1 after excitation-spike (ES) pairing; E was a weak basal dendritic excitation evoked by stratum oriens stimulation, and S was a population spike evoked by stratum radiatum apical dendritic excitation. We hypothesize that positive ES pairing-generating synaptic excitation before a spike-results in long-term potentiation (LTP) while negative ES pairing results in long-term depression (LTD). Pairing (50 pairs at 5 Hz) at ES intervals of -10 to 0 ms resulted in significant input-specific LTP of the basal dendritic excitatory sink, lasting 60-120 min. Pairing at +10- to +20-ms ES intervals, or unpaired 5-Hz stimulation, did not induce significant basal dendritic or apical dendritic LTP or LTD. No basal dendritic LTD was found after stimulation of stratum oriens with 200 pairs of high-intensity pulses at 25-ms interval. Pairing-induced LTP was abolished by pretreatment with an N-methyl-d-aspartate receptor antagonist, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), which also reduced spike bursting during 5-Hz pairing. Pairing at 0.5 Hz did not induce spike bursts or basal dendritic LTP. In conclusion, ES pairing at 5 Hz resulted in input-specific basal dendritic LTP at ES intervals of -10 ms to 0 ms but no LTD at ES intervals of -20 to +20 ms. Associative LTP likely occurred because of theta-rhythmic coincidence of subthreshold excitation with a backpropagated spike burst, which are conditions that can occur naturally in the hippocampus.

A Voltage-Based STDP Rule Combined with Fast BCM-Like Metaplasticity Accounts for LTP and Concurrent "Heterosynaptic" LTD in the Dentate Gyrus In Vivo.

Long-term potentiation (LTP) and long-term depression (LTD) are widely accepted to be synaptic mechanisms involved in learning and memory. It remains uncertain, however, which particular activity rules are utilized by hippocampal neurons to induce LTP and LTD in behaving animals. Recent experiments in the dentate gyrus of freely moving rats revealed an unexpected pattern of LTP and LTD from high-frequency perforant path stimulation. While 400 Hz theta-burst stimulation (400-TBS) and 400 Hz delta-burst stimulation (400-DBS) elicited substantial LTP of the tetanized medial path input and, concurrently, LTD of the non-tetanized lateral path input, 100 Hz theta-burst stimulation (100-TBS, a normally efficient LTP protocol for in vitro preparations) produced only weak LTP and concurrent LTD. Here we show in a biophysically realistic compartmental granule cell model that this pattern of results can be accounted for by a voltage-based spike-timing-dependent plasticity (STDP) rule combined with a relatively fast Bienenstock-Cooper-Munro (BCM)-like homeostatic metaplasticity rule, all on a background of ongoing spontaneous activity in the input fibers. Our results suggest that, at least for dentate granule cells, the interplay of STDP-BCM plasticity rules and ongoing pre- and postsynaptic background activity determines not only the degree of input-specific LTP elicited by various plasticity-inducing protocols, but also the degree of associated LTD in neighboring non-tetanized inputs, as generated by the ongoing constitutive activity at these synapses.

Long-term fluoxetine treatment induces input-specific LTP and LTD impairment and structural plasticity in the CA1 hippocampal subfield

Antidepressant drugs are usually administered for several weeks for the treatment of major depressive disorder. However, they are also prescribed in several additional psychiatric conditions as well as during long-term maintenance treatments. Antidepressants induce adaptive changes in several forebrain structures which include modifications at glutamatergic synapses. We recently found that repetitive administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine to naïve adult male rats induced an increase of mature, mushroom-type dendritic spines in several forebrain regions. This was associated with an increase of GluA2-containing α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPA-Rs) in telencephalic postsynaptic densities. To unravel the functional significance of such a synaptic re-arrangement, we focused on glutamate neurotransmission in the hippocampus. We evaluated the effect of four weeks of 0.7 mg/kg fluoxetine on long-term potentiation (LTP) and long-term depression (LTD) in the CA1 hippocampal subfield. Recordings in hippocampal slices revealed profound deficits in LTP and LTD at Schaffer collateral-CA1 synapses associated to increased spine density and enhanced presence of mushroom-type spines, as revealed by Golgi staining. However, the same treatment had neither an effect on spine morphology, nor on LTP and LTD at perforant path-CA1 synapses. Cobalt staining and immunohistochemical experiments revealed decreased AMPA-R Ca2+ permeability in the stratum radiatum (s.r.) together with increased GluA2-containing Ca2+ impermeable AMPA-Rs. Therefore, 4 weeks of fluoxetine treatment promoted structural and functional adaptations in CA1 neurons in a pathway-specific manner that were selectively associated with impairment of activity-dependent plasticity at Schaffer collateral-CA1 synapses.

High-frequency stimulation of the temporoammonic pathway induces input-specific long-term potentiation in subicular bursting cells

The subiculum (Sub) as a part of the hippocampal formation is thought to play a functional role in learning and memory. In addition to its major input from CA1 pyramidal cells, the subiculum receives input from the entorhinal cortex (EC) via the temporoammonic pathway. Thus far, synaptic plasticity in the subiculum was mainly investigated at CA1–Sub synapses. According to their spiking pattern, pyramidal cells in the subiculum were classified as bursting cells and non-bursting cells. In the present study, we demonstrate that subicular bursting cells show input-specific forms of long-term potentiation (LTP). At CA1–Sub synapses, bursting cells have been shown to express a presynaptic NMDA receptor-dependent LTP that depends on the activation of a cAMP–PKA cascade (Wozny et al., Journal of Physiology 2008). In contrast, at EC–Sub synapses the induction of LTP in bursting cells shows a high induction-threshold and relies on the activation of postsynaptic NMDA receptors, postsynaptic depolarization and postsynaptic Ca2+ influx. Each form of LTP is input-specific and fails to induce heterosynaptic plasticity. Taken together, our data suggest that distinct, input-specific mechanisms govern high frequency-induced LTP at subicular bursting cells' synapses.

The Curious Case of a Wandering Kinase: CaMKII Spreads the Wealth?

Calcium/calmodulin-dependent kinase II has been suggested to produce input-specific long-term potentiation of synaptic strength. This idea has been complicated by results from Rose, Jin, and Craig demonstrating that spatiotemporally restricted NMDA receptor excitation at contiguous synapses can result in the translocation of activated CaMKII throughout the dendritic arbor.

Locally dynamic synaptic learning rules in pyramidal neuron dendrites.

Long-term potentiation (LTP) of synaptic transmission underlies aspects of learning and memory. LTP is input-specific at the level of individual synapses, but neural network models predict interactions between plasticity at nearby synapses. Here we show in mouse hippocampal pyramidal cells that LTP at individual synapses reduces the threshold for potentiation at neighbouring synapses. After input-specific LTP induction by two-photon glutamate uncaging or by synaptic stimulation, subthreshold stimuli, which by themselves were too weak to trigger LTP, caused robust LTP and spine enlargement at neighbouring spines. Furthermore, LTP induction broadened the presynaptic-postsynaptic spike interval for spike-timing-dependent LTP within a dendritic neighbourhood. The reduction in the threshold for LTP induction lasted approximately 10 min and spread over approximately 10 microm of dendrite. These local interactions between neighbouring synapses support clustered plasticity models of memory storage and could allow for the binding of behaviourally linked information on the same dendritic branch.

Spatiotemporal Asymmetry of Associative Synaptic Plasticity in Fear Conditioning Pathways

Input-specific long-term potentiation (LTP) in afferent inputs to the amygdala serves an essential function in the acquisition of fear memory. Factors underlying input specificity of synaptic modifications implicated in information transfer in fear conditioning pathways remain unclear. Here we show that the strength of naive synapses in two auditory inputs converging on a single neuron in the lateral nucleus of the amygdala (LA) is only modified when a postsynaptic action potential closely follows a synaptic response. The stronger inhibitory drive in thalamic pathway, as compared with cortical input, hampers the induction of LTP at thalamo-amygdala synapses, contributing to the spatial specificity of LTP in convergent inputs. These results indicate that spike timing-dependent synaptic plasticity in afferent projections to the LA is both temporarily and spatially asymmetric, thus providing a mechanism for the conditioned stimulus discrimination during fear behavior.

Late-associativity, synaptic tagging, and the role of dopamine during LTP and LTD

Protein synthesis-dependent, synapse input-specific late phases of long-term potentiation (LTP) and depression (LTD) may underlie memory formation at the cellular level. Recently, it was described that the induction of LTP can mark a specifically activated synapse by a synaptic tag to capture synapse non-specific plasticity-related proteins (PRPs) and thus maintaining input-specific LTP for prolonged periods. Here we show in rat hippocampal slices in vitro, that the induction of protein synthesis-dependent late-LTD is also characterized by synaptic tagging and that heterosynaptic induction of either LTD or LTP on two sets of independent synaptic inputs S1 and S2 can lead to late-associative interactions: early-LTD in S2 was transformed into a late-LTD, if late-LTP was induced in S1. The synthesis of process-independent PRPs by late-LTP in S1 was sufficient to transform early- into late-LTD in S2 when process-specific synaptic tags were set. We name this new associative property of cellular information processing ‘cross-tagging.’

Input-specific LTP and depotentiation in the basolateral amygdala.

The amygdala plays a central role in emotional memory. The cellular mechanisms by which the amygdala participates in emotional learning are believed to be changes in efficacy of synaptic transmission, similar to long-term potentiation (LTP) and long-term depression (LTD). Although different forms of LTP have been shown in the amygdala, many of their features are still unknown. Here, we use both field potential and intracellular recordings in rat amygdala slices, and show that LTP in the basolateral nucleus, induced by high-frequency stimulation (HFS) of the external capsule is input-specific, can be reversed by low-frequency stimulation (LFS), and can be reinstated by HFS. These synapse-specific, reversible changes in synaptic strength in the basolateral nucleus of the amygdala may be important to amygdala's role in emotional memory.

A repetitive intracortical microstimulation pattern induces long-lasting synaptic depression in brain slices of the rat primary somatosensory cortex.

Repetitive intracortical microstimulation (ICMS) applied to the rat primary somatosensory cortex (SI) in vivo was reported to induce reorganization of receptive fields and cortical maps. The present study was designed to examine the effect of such an ICMS pattern applied to layer IV of brain slices containing SI on the efficacy of synaptic input to layer II/III. Effects of ICMS on the synaptic strength was quantified for the first synaptic component (s1) of cortical field potentials (FPs) recorded from layer II/III of SI. FPs were evoked by stimulation in layer IV. The pattern of ICMS was identical to that used in vivo. However, stimulation intensity had to be raised to induce an alteration of synaptic strength. In brain slices superfused with standard ACSF, repetitive ICMS induced a short-lasting (60 min) reduction of the amplitude (-37%) and the slope (-61%) of s1 evoked from the ICMS site, while the amplitude and the slope of s1 evoked from a control stimulation site in cortical layer IV underwent a slow onset increase (13% and 50%, respectively). In brain slices superfused with ACSF containing 1.25 microM bicuculline, ICMS induced an initial strong reduction of the amplitude (-50%) and the slope (-79%) of s1 evoked from the ICMS site. These effects decayed to a sustained level of depression by -30% (amplitude) and -60% (slope). In contrast to experiments using standard ACSF, s1 evoked from the control site was not affected by ICMS. The presynaptic volley was not affected in either of the two groups of experiments. A conventional high frequency stimulation (HFS) protocol induced input-specific long-term potentiation (LTP) of the amplitude and slope of s1 (25% and 76%, respectively). Low frequency stimulation (LFS) induced input-specific long-term depression (LTD) of the amplitude and slope of s1 (24% and 30%, respectively). Application of common forms of conditioning stimulation (HFS and LFS) resulted in LTP or LTD of s1, indicating normal susceptibility of the brain slices studied to the induction of common forms of synaptic plasticity. Therefore, the effects of repetitive ICMS on synaptic FP components were considered ICMS-specific forms of short-lasting (standard ACSF) or long-lasting synaptic depression (ACSF containing bicuculline), the latter resembling neocortical LTD. Results of this study suggest that synaptic depression of excitatory mechanisms are involved in the cortical reorganization induced by repetitive ICMS in vivo. An additional contribution of an ICMS-induced modification of inhibitory mechanisms to cortical reorganization is discussed.

Synaptic Transmission and Hippocampal Long-Term Potentiation in Transgenic Mice Expressing FAD-Linked Presenilin 1

Mutations in two related genes, presenilin 1 and presenilin 2 (PS1andPS2), cause a subset of early-onset familial Alzheimer's disease (FAD). PS1 is expressed in a variety of neuronal and peripheral tissues, including neuronal populations known to be at risk in Alzheimer's disease such as CA1 hippocampal neurons. To examine whether FAD-linked mutations in PS1 directly influence the physiology of learning and memory, we measured the field excitatory postsynaptic potential (fEPSP) at the Schaffer collateral-CA1 synapse in hippocampal slices. Basal synaptic transmission and long-term potentiation (LTP) were examined in neurons of transgenic mice expressing wild-type human PS1 (WtTg) and FAD-linked A246E PS1 variant (MTg) and in neurons of nontransgenic littermates (NTg). Several measures of basal synaptic transmission were unaltered in WtTg and MTg compared to NTg mice, including maximum fEPSP slope, maximum fEPSP amplitude, maximum fiber volley amplitude, and the function relating fiber volley amplitude to fEPSP slope, an index of basal synaptic strength. In addition, paired-pulse facilitation was not changed. However, upon theta burst stimulation or high-frequency stimulation, input-specific LTP in MTg animals had a larger initial amplitude and was more persistent than that in WtTg or NTg animals. These data suggest that the FAD-linked A246E variant of PS1 leads to higher degree of LTP induction in mice.

NMDA receptor dependence of the input specific NMDA receptor-independent LTP in the hippocampal CA1 region

An important characteristic of long-term potentiation (LTP) in the hippocampal CA1 region is that it is specific for those synapses which are active during the induction event. This input specificity is commonly attributed to the location and properties of the N-methyl- d-aspartate (NMDA) receptor channel. Experiments using strong high-frequency orthodromic activation have suggested that input-specific LTP can occur also in the absence of NMDA receptor activation. The present experiments have re-examined this question. They were performed in the CA1 region of hippocampal slices, and the synaptic strength was evaluated from the initial slope of the dendritically recorded field potential. In agreement with previous reports, 0.5 s. 200 Hz, orthodromic trains were found to lead to a substantial input-specific LTP (averaging 62%) in the presence of the competitive NMDA receptor antagonist d-(−)-2-amino-5-phosphonopentanoic acid ( d-AP5) (20 μM). Under conditions of higher NMDA receptor blockade considerably less LTP was evoked. In 50 μM d-AP5 and 20 μM chloro-kynurenate LTP averaged 13.4%, and after addition of 20 μM (+)-dizicilpine malcate (MK-801) LTP averaged 5.9%. On the other hand, in 20 μM d-AP5 and 20 μM of the calcium channel antagonist nifedipine LTP averaged 49.9%. The present results suggest that NMDA receptor activity remaining in high concentrations of AP5 is sufficient to underly LTP induction under strong induction conditions.

Long-term potentiation in the in vitro perirhinal cortex displays associative properties

Brief high frequency tetanization trains reliably induced input-specific long-term potentiation (LTP) in slices of rat perirhinal cortex maintained in vitro. Furthermore, associative interactions between inputs were observed following simultaneous tetanization of separate inputs. This associativity may be mediated via NMDA receptors as LTP was blocked in the presence of APV. These results suggest that LTP may underlie the participation of perirhinal cortex in memory processes.

Long-term potentiation in the hippocampal CA1 region in the presence ofN-methyl-d-aspartate receptor antagonists

The present study deals with the question of whether L-type voltage-gated calcium channels can support the induction of input specific long-term potentiation. Tetanus-induced potentiation of synaptic transmission was examined in the CA1 region of normal and disinhibited guinea-pig hippocampal slices. It was found that afferent tetanization in the presence of 50 microM of the N-methyl-D-aspartate receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid led to a prolonged input specific potentiation. This potentiation was found only in disinhibited slices, its induction required cooperativity, and it was associated with an increase in the early part of the field excitatory postsynaptic potential initial slope. It was not affected by the L-type voltage-gated calcium channel blocker nifedipine, but it was reduced when D(-)-2-amino-5-phosphonopentanoic acid was supplemented with other N-methyl-D-aspartate receptor antagonists. The present study also examined a potentiation that was not restricted to the activated synapses and that was not associated with an increase in the early part of the field excitatory postsynaptic potential initial slope. This potentiation was blocked by the L-type voltage-gated calcium channel antagonist nifedipine. It is concluded that calcium influx through L-type voltage-gated calcium channels participates in the generation of a prolonged potentiation, but not of the input specific N-methyl-D-aspartate receptor-dependent long-term potentiation. The results also suggest that high concentrations of D(-)-2-amino-5-phosphonopentanoic acid can be insufficient to fully prevent N-methyl-D-aspartate receptor activation by strong afferent tetanization in the disinhibited slice.