Properties of long-term synaptic plasticity and metaplasticity in organotypic slice cultures of rat hippocampus

The aim of this study was to investigate whether synaptic plasticity and metaplasticity in slice cultures of the young rat hippocampus were comparable to previously reported synaptic plasticity and metaplasticity in acute adult hippocampal slices. This is relevant since differences do exist between the preparations as a result of age and the ex vivo maintenance. We prepared and maintained slice cultures from 5- to 6-day-old rats according to the porous membrane method. After 12–16 days in vitro, extracellular low-frequency stimulation (LFS) and high-frequency stimulation (HFS) protocols were applied to the Schaffer collaterals, and extracellular field potentials were recorded in area CA1. LFS and HFS induced long-term depression (LTD) and long-term potentiation (LTP), respectively. LTP could be reversed by LFS, as could LTD by HFS 60 min after induction. Plotting the amount of LTD and LTP versus stimulation protocol demonstrated frequency-dependence of the sign and extent of plasticity. Priming activation of group 1 metabotropic glutamate receptors (mGluRs) with DHPG facilitated subsequent LTP, revealing a metaplastic effect similar to that observed in acute slices. Immunohistochemistry for group 1 mGluR subtypes mGluR1α and mGluR5 showed both receptors to be present in these cultures. We conclude that synaptic plasticity and mGluR-mediated metaplasticity are largely comparable to those effects found in acute in vitro techniques.     

LTP of GABAergic synapses in the ventral tegmental area and beyond

One of the mechanisms by which the experience-dependent reorganization of neural circuitry can occur is through changes in synaptic strength. Almost every excitatory synapse in the mammalian brain exhibits LTP (long-term potentiation) or LTD (long-term depression), two cellular mechanisms of synaptic plasticity. However, LTP and LTD have been reported much more rarely at fast inhibitory GABA_A receptor synapses. Our recent study suggests that in vivo morphine initiates a long-lasting alteration of GABAergic synapses in the ventral tegmental area (VTA) by blocking the mechanisms required for LTP of GABAergic synapses. Here we put this work into the context of other examples of synaptic plasticity at GABAergic synapses.     

Molecular mechanism for loss of visual cortical responsiveness following brief monocular deprivation

A dramatic form of experience-dependent synaptic plasticity is revealed in visual cortex when one eye is temporarily deprived of vision during early postnatal life. Monocular deprivation (MD) alters synaptic transmission such that cortical neurons cease to respond to stimulation of the deprived eye, but how this occurs is poorly understood. Here we show in rat visual cortex that brief MD sets in motion the same molecular and functional changes as the experimental model of homosynaptic long-term depression (LTD), and that prior synaptic depression by MD occludes subsequent induction of LTD. The mechanisms of LTD, about which there is now a detailed understanding, therefore contribute to visual cortical plasticity.     

The sliding threshold of modification hypothesis: application to the effect of hypothyroidism or chronic psychosocial stress and nicotine on synaptic plasticity

The Bienenstock, Cooper, and Munro (BCM) theory or the sliding threshold model can be used to explain the changes in synaptic plasticity related to learning and memory, namely long-term potentiation (LTP) and depression (LTD). In this study, we applied synaptic plasticity changes induced by either chronic psychosocial stress or hypothyroidism, and their restoration by chronic nicotine treatment, to the sliding threshold model. Psychosocial stress- or hypothyroidism-induced changes in synaptic plasticity generated a shift in the sliding threshold of modification (θ_m) toward LTD. In addition, chronic nicotine treatment restored the θ_m to the normal position by normalizing psychosocial stress- or hypothyroidism-induced impairment of LTP and enhancement of LTD. The data correlate with our previous findings: a shift in the balance of kinase/phosphatase toward phosphatase during psychosocial stress or hypothyroidism, which is restored by chronic nicotine treatment.     

Bidirectional long-term motor cortical plasticity and metaplasticity induced by quadripulse transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising tool to induce plastic changes that are thought in some cases to reflect N -methyl- d -aspartate-sensitive changes in synaptic efficacy. As in animal experiments, there is some evidence that the sign of rTMS-induced plasticity depends on the prior history of cortical activity, conforming to the Bienenstock–Cooper–Munro (BCM) theory. However, experiments exploring these plastic changes have only examined priming-induced effects on a limited number of rTMS protocols, often using designs in which the priming alone had a larger effect than the principle conditioning protocol. The aim of this study was to introduce a new rTMS protocol that gives a broad range of after-effects from suppression to facilitation and then test how each of these is affected by a priming protocol that on its own has no effect on motor cortical excitability, as indexed by motor-evoked potential (MEP). Repeated trains of four monophasic TMS pulses (quadripulse stimulation: QPS) separated by interstimulus intervals of 1.5–1250 ms produced a range of after-effects that were compatible with changes in synaptic plasticity. Thus, QPS at short intervals facilitated MEPs for more than 75 min, whereas QPS at long intervals suppressed MEPs for more than 75 min. Paired-pulse TMS experiments exploring intracortical inhibition and facilitation after QPS revealed effects on excitatory but not inhibitory circuits of the primary motor cortex. Finally, the effect of priming protocols on QPS-induced plasticity was consistent with a BCM-like model of priming that shifts the crossover point at which synaptic plasticity reverses from depression to potentiation. The broad range of after-effects produced by the new rTMS protocol opens up new possibilities for detailed examination of theories of metaplasticity in humans.     

Long-term depression induced by sensory deprivation during cortical map plasticity in vivo

Cortical map plasticity is thought to involve long-term depression (LTD) of cortical synapses, but direct evidence for LTD during plasticity or learning in vivo is lacking. One putative role for LTD is in the reduction of cortical responsiveness to behaviorally irrelevant or unused sensory stimuli, a common feature of map plasticity. Here we show that whisker deprivation, a manipulation that drives map plasticity in rat somatosensory cortex (S1), induces detectable LTD-like depression at intracortical excitatory synapses between cortical layer 4 (L4) and L2/3 pyramidal neurons. This synaptic depression occluded further LTD, enhanced LTP, was column specific, and was driven in part by competition between active and inactive whiskers. The synaptic locus of LTD and these properties suggest that LTD underlies the reduction of cortical responses to deprived whiskers, a major component of S1 map plasticity.     

Primary motor cortical metaplasticity induced by priming over the supplementary motor area

Motor cortical plasticity induced by repetitive transcranial magnetic stimulation (rTMS) sometimes depends on the prior history of neuronal activity. These effects of preceding stimulation on subsequent rTMS-induced plasticity have been suggested to share a similar mechanism to that of metaplasticity, a homeostatic regulation of synaptic plasticity. To explore metaplasticity in humans, many investigations have used designs in which both priming and conditioning are applied over the primary motor cortex (M1), but the effects of priming stimulation over other motor-related cortical areas have not been well documented. Since the supplementary motor area (SMA) has anatomical and functional cortico-cortical connections with M1, here we studied the homeostatic effects of priming stimulation over the SMA on subsequent rTMS-induced plasticity of M1. For priming and subsequent conditioning, we employed a new rTMS protocol, quadripulse stimulation (QPS), which produces a broad range of motor cortical plasticity depending on the interval of the pulses within a burst. The plastic changes induced by QPS at various intervals were altered by priming stimulation over the SMA, which did not change motor-evoked potential sizes on its own but specifically modulated the excitatory I-wave circuits. The data support the view that the homeostatic changes are mediated via mechanisms of metaplasticity and highlight an important interplay between M1 and SMA regarding homeostatic plasticity in humans.     

Interactions between LTP- and LTD-inducing stimulation in the sensorimotor cortex of the awake freely moving rat

Bidirectional modifications in synaptic efficacy are central components in models of cortical learning and memory. More recently, the regulation of synaptic plasticity according to the history of synaptic activation, termed "metaplasticity," has become a focus of research on the physiology of memory. Here we explore such interactions between long-term potentiation (LTP) and long-term depression (LTD) in the chronically prepared rat. The effects of successive high- and low-frequency stimulation were examined in sensorimotor cortex in the adult, freely moving rat. High-frequency (300 Hz) stimulation (HFS) applied to the white matter was used to induce LTP, and prolonged, low-frequency (1 Hz) stimulation (LFS) was used to induce either depotentiation or LTD. Combined stimulation (HFS/LFS or LFS/HFS) during the induction phase attenuated potentiation effects only if the LFS followed the HFS. LTD induced by LFS alone was expressed as a reduction in the amplitude of both short- and long-latency field potential components, whereas depotentiation was primarily expressed as a decrease in the amplitude of the potentiated long-latency component. In other experiments, LTP (or LTD) was induced to asymptotic levels before applying LFS (or HFS). LFS caused depotentiation of the late component but had no measurable effect on the early component. HFS reversed previously induced LTD, but the potentiation decayed more rapidly than usual. LTP and LTD therefore modulate each other in the awake, behaving rat.     

Serotonin increases the incidence of primary afferent-evoked long-term depression in rat deep dorsal horn neurons

5-hydroxytryptamine (5-HT) is released in spinal cord by descending systems that modulate somatosensory transmission and can potently depress primary afferent-evoked synaptic responses in dorsal horn neurons. Since primary afferent activity-induced long-term potentiation (LTP) may contribute to central sensitization of nociception, we studied the effects of 5-HT on the expression of sensory-evoked LTP and long-term depression (LTD) in deep dorsal horn (DDH) neurons. Whole cell, predominantly current clamp, recordings were obtained from DDH neurons in transverse slices of neonatal rat lumbar spinal cord. The effect of 5-HT on dorsal-root stimulation-evoked synaptic responses was tested before, during, or after high-frequency conditioning stimulation (CS). In most cells (80%), 5-HT caused a depression of the na?ve synaptic response. Even though 5-HT depressed evoked responses, CS in the presence of 5-HT was not only still capable of inducing LTD but also increased its incidence from 54% in controls to 88% (P < 0.001). Activation of ligands selective for 5-HT(1A/1B) and 5-HT(1B), but not 5-HT(2A/2C) or 5-HT(3) receptors, best reproduced these actions. 5-HT also potently depressed postconditioning synaptic responses regardless of whether the induced plasticity was LTP or LTD. Our results demonstrate that in addition to depressing the amplitude of evoked sensory input, 5-HT can also control the direction of its long-term modifiability, favoring the expression of LTD. These findings demonstrate cellular mechanisms that may contribute to the descending serotonergic control of nociception.     

Protein kinase CK2 modulates synaptic plasticity by modification of synaptic NMDA receptors in the hippocampus

Synaptic plasticity is the foundation of learning and memory. The protein kinase CK2 phosphorylates many proteins related to synaptic plasticity, but whether it is directly involved in it has not been clarified. Here, we examined the role of CK2 in synaptic plasticity in hippocampal slices using the CK2 selective inhibitors 5,6-dichloro-1-β- d -ribofuranosylbenzimidazole (DRB) and 4,5,6,7-tetrabromobenzotriazole (TBB). These significantly inhibited N -methyl- d -aspartate (NMDA) receptor-dependent long-term potentiation (LTP). DRB also inhibited NMDA receptor-mediated synaptic transmission, while leaving NMDA receptor-independent LTP unaffected. NMDA receptors thus appear to be the primary targets of CK2. Although both long-term depression (LTD) and LTP are induced by the influx of Ca²⁺ through NMDA receptors, surprisingly, LTD was not affected by CK2 inhibitors. We postulated that the LTP-selective modulation by CK2 is due to selective modulation of NMDA receptors, and tested two hypotheses concerning the modulation of NMDA receptors: (i) CK2 selectively modulates NR2A subunits possibly related to LTP, but not NR2B subunits possibly related to LTD; and (ii) CK2 selectively affects synaptic but not extrasynaptic NMDA receptors whose activation is sufficient to induce LTD. DRB decreased NMDA receptor-mediated synaptic transmission in the presence of selective NR2A subunit antagonist. The former hypothesis thus appears unlikely to be correct. However, DRB decreased synaptic NMDA receptor responses in cultured hippocampal neurons without affecting extrasynaptic NMDA receptor current. These findings support the latter hypothesis, that CK2 selectively affects LTP by selective modification of synaptic NMDA receptors in a receptor-location-specific manner.     

Spike timing-dependent plasticity: a learning rule for dendritic integration in rat CA1 pyramidal neurons

Long-term plasticity of dendritic integration is induced in parallel with long-term potentiation (LTP) or depression (LTD) based on presynaptic activity patterns. It is, however, not clear whether synaptic plasticity induced by temporal pairing of pre- and postsynaptic activity is also associated with synergistic modification in dendritic integration. We show here that the spike timing-dependent plasticity (STDP) rule accounts for long-term changes in dendritic integration in CA1 pyramidal neurons in vitro . Positively correlated pre- and postsynaptic activity (delay: +5/+50 ms) induced LTP and facilitated dendritic integration. Negatively correlated activity (delay: −5/−50 ms) induced LTD and depressed dendritic integration. These changes were not observed following positive or negative pairing with long delays (> ±50 ms) or when NMDA receptors were blocked. The amplitude–slope relation of the EPSP was facilitated after LTP and depressed after LTD. These effects could be mimicked by voltage-gated channel blockers, suggesting that the induced changes in EPSP waveform involve the regulation of voltage-gated channel activity. Importantly, amplitude–slope changes induced by STDP were found to be input specific, indicating that the underlying changes in excitability are restricted to a limited portion of the dendrites. We conclude that STDP is a common learning rule for long-term plasticity of both synaptic transmission and dendritic integration, thus constituting a form of functional redundancy that insures significant changes in the neuronal output when synaptic plasticity is induced.     

Dynamic synapses as archives of synaptic history: state-dependent redistribution of synaptic efficacy in the rat hippocampal CA1

Plastic modifications of synaptic strength are putative mechanisms underlying information processing in the brain, including memory storage, signal integration and filtering. Here we describe a dynamic interplay between short-term and long-term synaptic plasticity. At rat hippocampal CA1 synapses, induction of both long-term potentiation (LTP) and depression (LTD) was accompanied by changes in the profile of short-term plasticity, termed redistribution of synaptic efficacy (RSE). RSE was presynaptically expressed and associated in part with a persistent alteration in hyperpolarization-activated I _h channel activity. Already potentiated synapses were still capable of showing RSE in response to additional LTP-triggering stimulation. Strikingly, RSE took place even after reversal of LTP or LTD, that is, the same synapse can display different levels of short-term plasticity without changing synaptic efficacy for the initial spike in burst presynaptic firing, thereby modulating spike transmission in a firing rate-dependent manner. Thus, the history of long-term synaptic plasticity is registered in the form of short-term plasticity, and RSE extends the information storage capacity of a synapse and adds another dimension of functional complexity to neuronal operations.     

GABAA receptor inhibition does not affect mGluR-dependent LTD at hippocampal Schaffer collateral-CA1 synapses

Hippocampal synaptic plasticity between Schaffer collaterals and CA1 pyramidal neurons can be induced by activation of N-methyl-d-aspartate receptors (NMDARs) or of metabotropic glutamate receptors (mGluRs). Inhibitory GABAergic interneurons in this region abundantly terminate on pyramidal neurons and may thus influence synaptic plasticity. Although NMDAR-dependent synaptic plasticity is known to be influenced by inhibitory interneurons, little is known about the role of GABA on mGluR-dependent plasticity. Here, we used field potential recordings of the Schaffer collateral-CA1 synapses in rat hippocampal slices in order to study the effect of GABA_A receptor (GABA_AR) inhibition on mGluR-dependent long-term depression (LTD). Without GABA_AR blockade, mGluR-dependent LTD was induced pharmacologically by the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG, 100 μM, 10 min) as well as electrically by paired-pulse low-frequency stimulation (PP-LFS, 900 paired pulses at 1 Hz) resulting in a stable depression of the field response lasting at least 80 min after LTD induction. The GABA_AR antagonist gabazine (5 μM) itself caused an increase of field responses suggesting an endogenous GABA release inhibiting CA1 field potentials. However, when either DHPG or PP-LFS was applied during GABA_AR inhibition, the field responses were significantly reduced. Moreover, normalizing these responses to experiments without GABA_AR blockade, there was no significant effect of gabazine on both DHPG- and PP-LFS-induced LTD. Thus, our results show that mGluR-dependent LTD at Schaffer collateral-CA1 synapses is unaffected by GABA_AR mediated synaptic transmission.     

Inhibiting dopamine reuptake blocks the induction of long-term potentiation and depression in the lateral entorhinal cortex of awake rats

Synaptic plasticity in olfactory inputs to the lateral entorhinal cortex may result in lasting changes in the processing of olfactory stimuli. Changes in dopaminergic tone can have strong effects on basal evoked synaptic responses in the superficial layers of the entorhinal cortex, and the current study investigated whether dopamine may modulate the induction of long-term potentiation (LTP) and depression (LTD) in piriform cortex inputs to layer II of the lateral entorhinal cortex in awake rats. Groups of animals were pretreated with either saline or the selective dopamine reuptake inhibitor GBR12909 prior to low or high frequency stimulation to induce LTD or LTP. In saline-treated groups, synaptic responses were potentiated to 122.4 ± 6.4% of baseline levels following LTP induction, and were reduced to 84.5 ± 4.9% following induction of LTD. Changes in synaptic responses were maintained for up to 60 min and returned to baseline levels within 24 h. In contrast, induction of both LTP and LTD was blocked in rats pretreated with GBR12909. Dopaminergic suppression of synaptic plasticity in the entorhinal cortex may serve to restrain activity-dependent plasticity during reward-relevant behavioral states or during processing of novel stimuli.     

Age-dependent decline in supragranular long-term synaptic plasticity by increased inhibition during the critical period in the rat primary visual cortex

Supragranular long-term potentiation (LTP) and depression (LTD) are continuously induced in the pathway from layer 4 during the critical period in the rodent primary visual cortex, which limits the use of supragranular long-term synaptic plasticity as a synaptic model for the mechanism of ocular dominance (OD) plasticity. The results of the present study demonstrate that the pulse duration of extracellular stimulation to evoke a field potential (FP) is critical to induction of LTP and LTD in this pathway. LTP and LTD were induced in the pathway from layer 4 to layer 2/3 in slices from 3-wk-old rats when FPs were evoked by 0.1- and 0.2-ms pulses. LTP and LTD were induced in slices from 5-wk-old rats when evoked by stimulation with a 0.2-ms pulse but not by stimulation with a 0.1-ms pulse. Both the inhibitory component of FP and the inhibitory/excitatory postsynaptic potential amplitude ratio evoked by stimulation with a 0.1-ms pulse were greater than the values elicited by a 0.2-ms pulse. Stimulation with a 0.1-ms pulse at various intensities that showed the similar inhibitory FP component with the 0.2-ms pulse induced both LTD and LTP in 5-wk-old rats. Thus extracellular stimulation with shorter-duration pulses at higher intensity resulted in greater inhibition than that observed with longer-duration pulses at low intensity. This increased inhibition might be involved in the age-dependent decline of synaptic plasticity during the critical period. These results provide an alternative synaptic model for the mechanism of OD plasticity.     

Aging effects on the limits and stability of long-term synaptic potentiation and depression in rat hippocampal area CA1

Altered hippocampal synaptic plasticity may underlie age-related memory impairment. In acute hippocampal slices from aged (22-24 mo) and young adult (1-12 mo) male Brown Norway rats, extracellular excitatory postsynaptic field potentials were recorded in CA1 stratum radiatum evoked by Schaffer collateral stimulation. We used enhanced Ca(2+) to Mg(2+) ratio and paired-pulse stimulation protocol to induce maximum changes in the synaptic plasticity. Six episodes of theta-burst stimulation (TBS) or nine episodes of paired low-frequency stimulation (pLFS) were used to generate asymptotic long-term potentiation (LTP) and long-term depression (LTD), respectively. In addition, long-term depotentiation (LTdeP) or de-depression (LTdeD) from maximal LTP and LTD were examined using two episodes of pLFS or TBS. Multiple episodes of TBS or pLFS produced significant LTP or LTD in aged and young adult rats; this was not different between age groups. Moreover, there was no significant difference in the amount of LTdeP or LTdeD between aged and young adult rats. Our results show no age differences in the asymptotic magnitude of LTP or LTD, rate of synaptic modifications, development rates, reversal, or decay after postconditioning. Thus impairment of the basic synaptic mechanisms responsible for expression of these forms of plasticity is not likely to account for decline in memory function within this age range.     

Bidirectional synaptic plasticity correlated with the magnitude of dendritic calcium transients above a threshold

The magnitude of postsynaptic Ca(2+) transients is thought to affect activity-dependent synaptic plasticity associated with learning and memory. Large Ca(2+) transients have been implicated in the induction of long-term potentiation (LTP), while smaller Ca(2+) transients have been associated with long-term depression (LTD). However, a direct relationship has not been demonstrated between Ca(2+) measurements and direction of synaptic plasticity in the same cells, using one induction protocol. Here, we used glutamate iontophoresis to induce Ca(2+) transients in hippocampal CA1 neurons injected with the Ca(2+)-indicator fura-2. Test stimulation of one or two synaptic pathways before and after iontophoresis showed that the direction of synaptic plasticity correlated with glutamate-induced Ca(2+) levels above a threshold, below which no plasticity occurred (approximately 180 nM). Relatively low Ca(2+) levels (180-500 nM) typically led to LTD of synaptic transmission and higher levels (>500 nM) often led to LTP. Failure to show plasticity correlated with Ca(2+) levels in two distinct ranges: <180 nM and approximately 450-600 nM, while only LTD occurred between these ranges. Our data support a class of models in which failure of Ca(2+) transients to affect transmission may arise either from insufficient Ca(2+) to affect Ca(2+)-sensitive proteins regulating synaptic strength through opposing activities or from higher Ca(2+) levels that reset activities of such proteins without affecting the net balance of activities. Our estimates of the threshold Ca(2+) level for LTD (approximately 180 nM) and for the transition from LTD to LTP (approximately 540 nM) may assist in constraining the molecular details of such models.     

Activity-dependent synaptic plasticity of NMDA receptors

Activity-dependent, bidirectional control of synaptic efficacy is thought to contribute to many forms of experience-dependent plasticity, including learning and memory. Although most excitatory synapses contain both AMPA and N -methyl- d -aspartate receptors (AMPARs and NMDARs), most studies have focused on the plasticity of synaptic AMPARs, and on the pivotal role of NMDA receptors for its induction. Here we review evidence that synaptic NMDARs themselves are subject to long-term activity-dependent changes by mechanisms that may differ from that of synaptic AMPARs. The bidirectional modulation of NMDAR-mediated synaptic responses is likely to have important functional implications for NMDAR-dependent forms of synaptic plasticity.     

Postsynaptic endocannabinoid release is critical to long-term depression in the striatum

The striatum functions critically in movement control and habit formation. The development and function of cortical input to the striatum are thought to be regulated by activity-dependent plasticity of corticostriatal glutamatergic synapses. Here we show that the induction of a form of striatal synaptic plasticity, long-term depression (LTD), is dependent on activation of the CB1 cannabinoid receptor. LTD was facilitated by blocking cellular endocannabinoid uptake, and postsynaptic loading of anandamide (AEA) produced presynaptic depression. The endocannabinoid necessary for striatal LTD is thus likely to be released postsynaptically as a retrograde messenger. These findings demonstrate a new role for endocannabinoids in the induction of long-term synaptic plasticity in a circuit necessary for habit formation and motor control.