Subsequent Induction Of Long-term Potentiation Research Articles

Brief environmental enrichment elicits metaplasticity on the insular cortex in vivo and reduces the strength of conditioned taste aversion

Environmental enrichment (EE) is known to improve memory and cognition and modulate the impact of aversive stimuli in animals, promoting the development of resilience to stressful situations. Likewise, it is known that EE can modulate synaptic plasticity as is the case of long-term potentiation (LTP). These findings have been described initially in ex vivo preparations, suggesting that the effects of EE are the result of an early modification of the synaptic excitability and transmission. In this regard, it is known that metaplasticity refers to the persistent modification, by previous activity, in the ability to induce synaptic plasticity. Our previous studies have shown that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of LTP in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) in vivo. In addition, we have shown that CTA extinction allows the induction but not the maintenance of IC-LTP of the Bla-IC pathway. Recently, we also showed that prior exposure to environmental enrichment for three weeks reduces the strength of CTA, restoring the brain-derived neurotrophic factor (BDNF) levels in the IC. The present study aimed to analyze the effects of brief exposure to an enriched environment on the strength of aversive memory, as well as on the in vivo IC-LTP. To do so, adult rats were exposed for seven days to an EE, either before CTA training or LTP induction in the Bla-IC pathway. Our results demonstrate that a seven-day exposure to an enriched environment attenuates the aversive response to a strong CTA and allows the induction but not the maintenance of LTP in the insular cortex. These findings provide evidence that metaplastic regulation in a neocortical region takes part in the mechanisms through which brief exposure to enriched environments attenuates an aversive response.

Adult-Onset Hypothyroidism Alters the Metaplastic Properties of Dentate Granule Cells by Decreasing Akt Phosphorylation.

The expression of homosynaptic long-term depression (LTD) governs the subsequent induction of long-term potentiation (LTP) at hippocampal synapses. This process, called metaplasticity, is associated with a transient increase in the levels of several kinases, such as extracellular signal-regulated protein kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and Akt kinase. It has been increasingly realized that the chemical changes in the hippocampus caused by hypothyroidism may be the key underlying causes of the learning deficits, memory loss, and impaired LTP associated with this disease. However, the functional role of thyroid hormones in the "plasticity of synaptic plasticity" has only begun to be elucidated. To address this issue, we sought to determine whether the administration of 6-n-propyl-2-thiouracil (PTU) alters the relationship between priming and the induction of subsequent LTP and related signaling molecules. The activation of ERK1/2, JNK, and Akt was measured in the hippocampus at least 95min after priming onset. We found that priming stimulation at 5Hz for 3s negatively impacted the induction of LTP by subsequent tetanic stimulation in hypothyroid animals, as manifested by a more rapid decrease in the fEPSP slope and population spike amplitude. This phenomenon was accompanied by lower levels of phosphorylated Akt in the surgically removed hippocampus of the hypothyroid rats compared to the euthyroid rats. The metaplastic response and the expression of these proteins in the 1-Hz-primed hippocampus were not different between the two groups. These observations suggest that decreased PI3K/Akt signaling may be involved in the compromised metaplastic regulation of LTP observed in hypothyroidism, which may account for the learning difficulties/cognitive impairments associated with this condition.

Extinction of aversive taste memory homeostatically prevents the maintenance of in vivo insular cortex LTP: Calcineurin participation.

Accumulating evidence indicates that homeostatic plasticity mechanisms dynamically adjust synaptic strength to promote stability that is crucial for memory storage. Our previous studies have shown that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of long-term potentiation (LTP) in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) in vivo. We have also reported that induction of LTP in the Bla-IC pathway modifies the CTA extinction. Memoryextinction involves the formation of a new associativememorythat inhibits a previously conditioned association. The aim of the present study was to analyze the effect of CTA extinction on the ability to induce subsequent LTP in the Bla-IC projection in vivo. Thus, 48 h after CTA extinction animals received high frequency stimulation in order to induce IC-LTP. Our results show that extinction training allows the induction but not the maintenance of IC-LTP. In addition, with the purpose of exploring part of the mechanisms involved in this process and since a body of evidence suggests that protein phosphatase calcineurin (CaN) is involved in the extinction of some behavioral tasks, we analyzed the participation of this phosphatase. The present results show that extinction training increases the CaN expression in the IC, as well as that the inhibition of this phosphatase reverts the effects of the CTA-extinction on the IC-LTP. These findings reveal that CTA extinction promotes a homeostatic regulation of subsequent IC synaptic plasticity maintenance through increases in CaN levels.

Prior activation of inositol 1,4,5-trisphosphate receptors suppresses the subsequent induction of long-term potentiation in hippocampal CA1 neurons.

We investigated the role of inositol 1,4,5-trisphosphate receptors (IP3Rs) activated by preconditioning low-frequency afferent stimulation (LFS) in the subsequent induction of long-term potentiation (LTP) in CA1 neurons in hippocampal slices from mature guinea pigs. Induction of LTP in the field excitatory postsynaptic potential or the population spike by the delivery of high-frequency stimulation (HFS, a tetanus of 100 pulses at 100 Hz) to the Schaffer collateral–commissural pathway to CA1 neuron synapses was suppressed when group I metabotropic glutamate receptors (mGluRs) were activated prior to the delivery of HFS. LTP induction was also suppressed when CA1 synapses were preconditioned 60 min before HFS by LFS of 1000 pulses at 1 Hz and this effect was inhibited when the test stimulation delivered at 0.05 Hz was either halted or applied in the presence of an antagonist of N-methyl-d-aspartate receptors, group I mGluRs, or IP3Rs during a 20-min period from 20 to 40 min after the end of LFS. Furthermore, blockade of group I mGluRs or IP3Rs immediately before the delivery of HFS overcame the effects of the preconditioning LFS on LTP induction. These results suggest that, in CA1 neurons, after a preconditioning LFS, activation of group I mGluRs caused by the test stimulation results in IP3Rs activation that leads to a failure of LTP induction.

Conditioned taste aversion prevents the long-lasting BDNF-induced enhancement of synaptic transmission in the insular cortex: A metaplastic effect

Homeostatic plasticity mechanisms dynamically adjust synaptic strengths to promote stability that is crucial for memory storage. Metaplasticity is an example of these forms of plasticity that modify the capacity of synapses to experience subsequent Hebbian modifications. In particular, training in several behavioral tasks modifies the ability to induce long-term potentiation (LTP). Recently, we have reported that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of LTP generated by high frequency stimulation in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC). One of the key molecular players that underlie long-term synaptic plasticity is brain-derived neurotrophic factor (BDNF). Previous studies from our group reported that acute microinfusion of BDNF in the IC induces a lasting potentiation of synaptic efficacy at the Bla-IC projection. Thus, the aim of the present study was to analyze whether CTA training modifies the ability to induce subsequent BDNF-induced potentiation of synaptic transmission in the Bla-IC projection in vivo. Accordingly, CTA trained rats received intracortical microinfusion of BDNF in order to induce lasting potentiation 48h after the aversion test. Our results show that CTA training prevents the induction of in vivo BDNF-LTP in the Bla-IC projection. The present results provide evidence that CTA modulates BDNF-dependent changes in IC synaptic strength.

Activation of inositol 1,4,5-trisphosphate receptors during preconditioning low-frequency stimulation suppresses subsequent induction of long-term potentiation in hippocampal CA1 neurons

We investigated the role of inositol 1,4,5-trisphosphate receptors (IP3Rs) activated during preconditioning low-frequency stimulation (LFS) in the subsequent high-frequency stimulation (HFS)-induced induction of long-term potentiation (LTP) in CA1 neurons in hippocampal slices from mature guinea pigs. Induction of LTP in the field excitatory postsynaptic potential (EPSP) or the population spike (PS) by delivery of HFS (a tetanus of 100 pulses at 100Hz) to the Schaffer collateral–commissural pathway to CA1 neuron synapses was suppressed when the CA1 synapses were preconditioned by LFS of 1000 pulses at 1Hz. This effect was inhibited when the preconditioning LFS was applied in the presence of an N-methyl-d-aspartate receptors (NMDARs) antagonist, a metabotropic glutamate receptor (mGluR) antagonist, IP3R antagonist, a calmodulin-dependent kinase II inhibitor or a calcineurin inhibitor. Furthermore, blockade of group I mGluRs immediately before the delivery of HFS blocked the inhibitory effect of the preconditioning LFS on subsequent induction of LTP by HFS. These results suggest that, in hippocampal CA1 neuron synapses, co-activation of NMDARs and IP3Rs during a preconditioning LFS results in both phosphorylation and dephosphorylation events that lead to prolonged activation of group I mGluRs that is responsible for the failure of LTP induction.

Metaplastic up-regulation of LTP in the rat visual cortex by monocular visual training: Requirement of task mastery, hemispheric specificity, and NMDA–GluN2B involvement

“Metaplasticity” is defined as an alteration of synaptic plasticity properties or mechanisms by a priming event without actual changes in synaptic strength. For example, visual discrimination training of rats leads to a facilitation of the subsequent induction of long-term potentiation (LTP) between the lateral geniculate nucleus (LGN) and the primary visual cortex (V1). Here, rats received visual discrimination training in a modified water maze, with one eye occluded during training to create monocular viewing conditions; 63% of rats acquired the task under these conditions. Following training, in vivo electrophysiology was used to examine LTP of field postsynaptic potentials (fPSPs) in V1 elicited by LGN stimulation. Rats that had successfully learned the task showed significantly greater LTP in the “trained V1” (contralateral to the open, trained eye) relative to the “untrained” hemisphere. Rats that underwent training but failed to acquire the task did not show this lateralized plasticity enhancement and had similar levels of LTP in both cerebral hemispheres. Cortical application of the NMDA receptor–GluN2B subunit antagonist Ro 25-6981 (2mM) reversed the training-induced LTP facilitation without affecting LTP in the untrained V1. Whole-cell patch clamp recordings of V1 (layers II/III) pyramidal cells in vitro demonstrated that pharmacologically isolated NMDA currents exhibit a greater sensitivity to GluN2B blockade in the trained relative to the untrained V1. Together, these experiments reveal a surprising degree of anatomical (only in the hemisphere contralateral to the trained eye) and behavioral specificity (only in rats that mastered the task) for the effect of visual training to enhance LTP in V1. Further, cortical GluN2B subunits appear to be directly involved in this metaplastic facilitation of thalamocortical plasticity, suggesting that NMDA subunit composition or functioning is, at least in part, regulated by the exposure to behaviorally significant stimuli in an animal’s sensory environment.

Metaplastic LTP inhibition after LTD induction in CA1 hippocampal slices involves NMDA Receptor-mediated Neurosteroidogenesis

Long-term depression (LTD) induced by low-frequency electrical stimulation (LFS) in the CA1 region of the hippocampus is a form of synaptic plasticity thought to contribute to learning and memory and to the pathophysiology of neuropsychiatric disorders. In naïve hippocampal slices from juvenile rats, we previously found that LTD induction can impair subsequent induction of long-term potentiation (LTP) via a form of N-methyl-d-aspartate receptor (NMDAR)-dependent metaplasticity, and have recently observed that pharmacologically induced NMDAR-dependent LTP inhibition involves 5α-reduced neurosteroids that augment the actions of γ-aminobutyric acid (GABA). In this study, we found that both LFS-induced LTD and subsequent inhibition of LTP induction involve neurosteroid synthesis via NMDAR activation. Furthermore, the timing of 5α-reductase inhibition relative to LFS can dissociate effects on LTD and metaplastic LTP inhibition. These findings indicate that 5α-reduced neurosteroids play an important role in synaptic plasticity and synaptic modulation in the hippocampus.

Suppressive effect of preconditioning low-frequency stimulation on subsequent induction of long-term potentiation by high frequency stimulation in hippocampal CA3 neurons

We investigated the role of inositol 1, 4, 5-trisphosphate receptors (IP3Rs), activated during preconditioning low-frequency afferent stimulation (LFS), in the subsequent induction of long-term potentiation (LTP) in CA3 neurons in hippocampal slices from mature guinea pigs. Induction of LTP in the field excitatory postsynaptic potential (EPSP) by the delivery of high-frequency stimulation (HFS, a tetanus of two trains of 100 pulses at 100Hz with a 10s interval) to mossy fiber-CA3 neuron synapses was suppressed when CA3 synapses were preconditioned by the LFS of 1000 pulses at 2Hz and this effect was inhibited when the LFS preconditioning was performed in the presence of an IP3R antagonist or a protein phosphatase inhibitor. Furthermore, activation of group 1 metabotropic glutamate receptors (mGluRs) during HFS canceled the effects of an IP3R antagonist given during preconditioning LFS on the subsequent LTP induction at mossy fiber-CA3 synapses. These results suggest that, in hippocampal mossy fiber-CA3 neuron synapses, activation of IP3Rs during a preconditioning LFS results in dephosphorylation events that lead to failure of the HFS to induce subsequent LTP.

PKMζ inhibition prevents the metaplastic change induced by conditioned taste aversion on insular cortex long-term potentiation in vivo

The activity history of a given neuron or pathway has been suggested to influence its future responses to synaptic inputs. In particular, training in several learning tasks produces a metaplastic change, that is, a change in the ability to induce subsequent synaptic plasticity. Experimental evidence shows that the maintenance of long term memory and long-term potentiation (LTP) requires the persistent action of the atypical protein kinase Cisoform, protein kinase M ζ (PKM ζ ). Recent work has demonstrated that the inactivation of PKM ζ in the insular cortex (IC) abolishes conditioned taste aversion (CTA) long term memory. Our previous studies in the IC have demonstrated that the induction of LTP in the basolateral amygdaloid nucleus (Bla)-IC projection previous to CTA training enhances the retention of this task. Moreover, recently, we have observed that CTA training blocks the subsequent induction of LTP in the Bla-IC projection. The aim of the present study was to investigate the participation of PKM ζon the CTA-dependent modification of the ability to induce subsequent LTP in the Bla-IC projection in vivo . Thus, we have delivered high-frequency stimulation in the Bla-IC projection in order to induce in vivo IC-LTP in the rats that underwent or did not have an impairment of CTA retention due to the intracortical administration of the selective PKM ζ pseudosubstrate inhibitory peptide, ZIP. Our results show that the microinfusion of ZIP into the IC of the behaving rats impairs long-term memory of CTA and prevents its effects on IC-LTP. These results indicate that PKM ζ is a key component of the cellular mechanisms necessary for the persistence of lasting memory traces as well as for those underlying metaplastic changes in neocortex, contributing to the persistence of aversive memories.

Conditioned taste aversion modifies persistently the subsequent induction of neocortical long-term potentiation in vivo

The ability of neurons to modify their synaptic strength in an activity-dependent manner has a crucial role in learning and memory processes. It has been proposed that homeostatic forms of plasticity might provide the global regulation necessary to maintain synaptic strength and plasticity within a functional dynamic range. Similarly, it is considered that the capacity of synapses to express plastic changes is itself subject to variation dependent on previous experience. In particular, training in several behavioral tasks modifies the possibility to induce long-term potentiation (LTP). Our previous studies in the insular cortex (IC) have shown that induction of LTP in the basolateral amygdaloid nucleus (Bla)-IC projection previous to conditioned taste aversion (CTA) training enhances the retention of this task. The aim of the present study was to analyze whether CTA training modifies the ability to induce subsequent LTP in the Bla-IC projection in vivo. Thus, CTA trained rats received high frequency stimulation in the Bla-IC projection in order to induce LTP 48, 72, 96 and 120h after the aversion test. Our results show that CTA training prevents the subsequent induction of LTP in the Bla-IC projection, for at least 120h after CTA training. We also showed that pharmacological inhibition of CTA consolidation with anisomycin (1μl/side; 100μg/μl) prevents the CTA effect on IC-LTP. These findings reveal that CTA training produces a persistent change in the ability to induce subsequent LTP in the Bla-IC projection in a protein-synthesis dependent manner, suggesting that changes in the ability to induce subsequent synaptic plasticity contribute to the formation and persistence of aversive memories.

Postnatal alterations in induction threshold and expression magnitude of long‐term potentiation and long‐term depression at hippocampal synapses

Activity-dependent synaptic plasticity refines neural networks during development and subserves information processing in adulthood. Previous research has revealed postnatal alterations in synaptic plasticity at nearly all forebrain synapses, suggesting different forms of synaptic plasticity may contribute to network development and information processing. To assess possible relationships between modifications in synaptic plasticity and maturation of cognitive ability, we examined excitatory synaptic function in area CA1 of the mouse hippocampus ∼3 weeks of age, when hippocampal-dependent learning and memory abilities first emerge. Long-term potentiation (LTP) and depression (LTD) of synaptic efficacy were observed in slices from juvenile animals younger than 3 weeks of age. Both pre- and postsynaptic mechanisms supported LTP and LTD in juveniles. After the third postnatal week, the magnitude of LTP was reduced and the threshold for postsynaptic induction was reduced, but the threshold for presynaptic induction was increased. The reduced threshold for postsynaptic LTP appeared to be due, partly, to an increase in baseline excitatory synaptic strength, which likely permitted greater postsynaptic depolarization during induction. Low frequency stimulation did not induce LTD at this more mature stage, but it blocked subsequent induction of LTP, suggesting metaplastic differences across age groups. Late postnatal modifications in activity-dependent synaptic plasticity might reflect attenuation of mechanisms more closely tied to network formation (presynaptic potentiation and pre- and postsynaptic depression) and unmasking of mechanisms underlying information processing and storage (associative postsynaptic potentiation), which likely impact the integrative capacity of the network and regulate the emergence of adult-like cognitive abilities.

Intrinsic Plasticity Complements Long-Term Potentiation in Parallel Fiber Input Gain Control in Cerebellar Purkinje Cells

Synaptic gain control and information storage in neural networks are mediated by alterations in synaptic transmission, such as in long-term potentiation (LTP). Here, we show using both in vitro and in vivo recordings from the rat cerebellum that tetanization protocols for the induction of LTP at parallel fiber (PF)-to-Purkinje cell synapses can also evoke increases in intrinsic excitability. This form of intrinsic plasticity shares with LTP a requirement for the activation of protein phosphatases 1, 2A, and 2B for induction. Purkinje cell intrinsic plasticity resembles CA1 hippocampal pyramidal cell intrinsic plasticity in that it requires activity of protein kinase A (PKA) and casein kinase 2 (CK2) and is mediated by a downregulation of SK-type calcium-sensitive K conductances. In addition, Purkinje cell intrinsic plasticity similarly results in enhanced spine calcium signaling. However, there are fundamental differences: first, while in the hippocampus increases in excitability result in a higher probability for LTP induction, intrinsic plasticity in Purkinje cells lowers the probability for subsequent LTP induction. Second, intrinsic plasticity raises the spontaneous spike frequency of Purkinje cells. The latter effect does not impair tonic spike firing in the target neurons of inhibitory Purkinje cell projections in the deep cerebellar nuclei, but lowers the Purkinje cell signal-to-noise ratio, thus reducing the PF readout. These observations suggest that intrinsic plasticity accompanies LTP of active PF synapses, while it reduces at weaker, nonpotentiated synapses the probability for subsequent potentiation and lowers the impact on the Purkinje cell output.

Properties of subsequent induction of long-term potentiation and/or depression in one synaptic input in apical dendrites of hippocampal CA1 neurons in vitro

The hippocampus is a prominent structure to study mechanisms of learning and memory at the cellular level. Long-term potentiation (LTP) as well as long-term depression (LTD) are the major cellular models which could underlie learning and memory formation. LTP and LTD consist of at least two phases, an early protein synthesis-independent transient stage (<4 h; E-LTP, E-LTD) as well as a prolonged phase (>4 h; L-LTP, L-LTD) requiring the synthesis of new proteins. It is known that during E-LTP the further induction of longer lasting LTP is precluded. However, if E-LTP is transformed into L-LTP, the same synapses now allow the induction of LTP again. We reproduced the LTP-results first and then investigated whether hippocampal LTP or LTD also prevents the establishment of subsequent LTD-induction in the same synaptic input. We show that the prior induction of LTP or LTD does not prevent a short-term depression (STD) but occludes LTD in apical dendrites of CA1 neurons in hippocampal slices in vitro during the early phase of LTP or LTD. However, LTD can again be induced in addition to STD after the establishment of L-LTP or L-LTD, that is about 4 h after the induction of the first event in the same synaptic input. We suggest that the neuronal input preserves the capacity for STD immediately after an initial potentiation or depression, but for the onset of additional longer lasting LTD in the same synaptic input, the establishment of the late plasticity form of the preceding event is critical.

Stress and Amygdala Suppression of Metaplasticity in the Medial Prefrontal Cortex

The term "metaplasticity" refers to the modulation of the ability to induce synaptic plasticity of the form of long-term potentiation (LTP) or long-term depression (LTD) following prior activation of the synapses. While often electrophysiological manipulations are used to demonstrate this phenomenon, prior behavioral manipulations such as exposure to stress were also found to affect the ability to induce LTP and LTD. Interestingly, amygdala stimulation was found to have effects on subsequent LTP induction that resemble those of stress. Here, we report that exposure to stress or basolateral amygdala (BLA) stimulation induces a form of metaplasticity, which prevents the ability of a second episode of stress or BLA activation to suppress LTP in the ventral hippocampus-medial prefrontal cortex (mPFC) pathway. This form of metaplasticity is N-methyl-D-aspartic acid (NMDA)-dependent since the injection of the NMDA partial agonist D-cycloserine prevented the inhibition of LTP induced by prior exposure of stress or BLA activation. Furthermore, blocking NMDA receptors by MK801 before the exposure to stress prevented the ability of the emotional manipulation to inhibit the subsequent modulation of plasticity, resulting in impaired LTP in the mPFC. Taken together, these findings demonstrate a new form of NMDA-dependent emotional metaplasticity in the ventral hippocampus-mPFC pathway.

Long-Term Potentiation of Excitatory Synapses on Neocortical Somatostatin-Expressing Interneurons

Synaptic plasticity has been extensively studied in principal neurons of the neocortex, but less work has been done on GABAergic interneurons. Interneurons consist of multiple subtypes and their synaptic properties vary between subtypes. In the present study, we have examined long-term potentiation (LTP) of excitatory synapses on somatostatin (SS)-expressing interneurons in neocortex using transgenic mice that express enhanced green fluorescent protein in these interneurons. We found that a strong theta burst stimulation was required to induce LTP in SS interneurons. LTP was associated with a reduction in paired-pulse facilitation and was not blocked by an N-methyl-d-aspartate receptor (NMDAR) antagonist. LTP was not affected by chelating postsynaptic Ca(2+) with BAPTA, a fast Ca(2+) chelator, and blocking L-type voltage-dependent Ca(2+) channels with nimodipine. Application of forskolin, an activator of adenylate cyclase that increases cyclic adenosine monophosphate (cAMP) concentration, enhanced synaptic transmission and occluded subsequent induction of LTP. Finally, we found that LTP was blocked by protein kinase A (PKA) inhibitors. Our results suggest that excitatory synapses on SS interneurons express a presynaptic form of LTP that is not dependent on NMDARs or postsynaptic Ca(2+) rise but is dependent on the cAMP-PKA signaling pathway.

Priming theta-burst repetitive transcranial magnetic stimulation with low- and high-frequency stimulation

Repetitive transcranial magnetic stimulation (rTMS) can be used to study metaplasticity in human motor cortex. The term metaplasticity describes a phenomenon where the prior synaptic history of a pathway can affect the subsequent induction of long-term potentiation or depression. In the current study, we investigated metaplasticity in human motor cortex with the use of inhibitory continuous theta-burst stimulation (cTBS). cTBS involves short bursts of high frequency (50 Hz) rTMS applied every 200 ms for 40 s. In the first series of experiments, cTBS was primed with 10 min of intermittent 2 or 6 Hz rTMS. Subjects (n = 20) received priming stimulation at 70% of active motor threshold or 90% of resting motor threshold. In another series of experiments, cTBS was primed with excitatory intermittent theta-burst stimulation (iTBS). iTBS involves a 2 s train of theta-burst stimulation delivered every 10 s for 190 s. Stimuli were delivered over the first dorsal interosseus motor area.. The effect of cTBS alone and primed cTBS on motor cortical excitability was investigated by recording motor-evoked potentials (MEP) in the first dorsal interosseus following single-pulse TMS. MEP area in the cTBS alone condition was not significantly different from cTBS primed with 2 or 6 Hz rTMS. However, priming cTBS with iTBS suppressed MEP area to a greater extent than in cTBS alone. Our results provide further evidence of metaplasticity in human motor cortex when appropriate priming protocols are employed.

Repetitive transcranial magnetic stimulation: faster or longer is not necessarily more

Since Donald Hebb postulated the ‘Hebb synapse’ where repetitive stimulation from the presynaptic cell increases synaptic efficacy and strengthens postsynaptic firing (Hebb, 1949), the theory of brain plasticity through synaptic modification has received considerable support. Long-term potentiation (LTP) and long-term depression (LTD) have been studied extensively in animals and are now being applied to humans. A method for modifying the excitability of the human brain is repetitive transcranial magnetic stimulation (rTMS), where trains of magnetic pulses are delivered and these pulses temporally summate to cause greater changes than a single pulse. These effects may outlast the stimulus train and vary from inhibition to facilitation, depending on the stimulus parameters, particularly the frequency. Many studies supported the notion that regular, high-frequency (2–30 Hz, Fig. 1A) stimulation increases cortical excitability (LTP-like effect) whereas low-frequency (0.3–1 Hz) stimulation decreases cortical excitability (LTD-like effect) (Hallett, 2007). Figure 1 Typical stimulus parameters used in four repetitive transcranial magnetic stimulation protocols More recently, stimulus parameters other than regular rTMS have been developed. Theta burst stimulation (TBS) was introduced as a potentially rapid and powerful method to induce cortical plasticity. It consists of repetitive blocks of pulses with different inter-block intervals (IBIs). Each block of pulses consists of trains of three TMS pulses at high frequency (50 Hz) and repeats at an inter-train interval (ITI) of 200 ms (Huang et al. 2005). The after-effects of TBS depend on the stimulus pattern, particularly the IBI. Continuous TBS (Fig. 1B) with a single block of stimuli leads to LTD-like effects. In contrast, intermittent TBS delivered at IBI of 10 s (Fig. 1C) leads to LTP-like effects. In this issue of The Journal of Physiology, Hamada et al. (2008) report a detailed study of a new rTMS protocol termed quadripulse stimulation (QPS) to further test the properties of irregular rTMS (Fig. 1D). Instead of biphasic pulses commonly used in rTMS, Hamada et al. employed four monophasic pulses as a single train and repeated at a fixed ITI of 5 s. They addressed an important question regarding the effects of different frequencies or interstimulus interval (ISI) within the train and showed that trains with short ISIs (1.5–10 ms, 100–667 Hz) produced LTP-like effects while trains with longer ISIs (30–100 ms, 10–33 Hz) produced LTD-like effects. However, the fastest stimulation at 1.5 ms ISI (667 Hz) produced less facilitation than ISI of 5 ms (200 Hz). Trains with even longer ISI (1250 ms) had no effect on motor cortex excitability. The results suggest high frequency QPS leads to an LTP-like effect while low frequency QPS leads to an LTD-like effect, similar to the findings in regular rTMS but the effective frequencies in QPS are much higher than that used in regular rTMS. Another important aspect of synaptic plasticity is that the threshold of LTP/LTD induction shifts as a function of the history of postsynaptic activity. This bidirectional property can be explained by the Bienenstock–Cooper–Munro (BCM) theory (Bienenstock et al. 1982). If LTP was activated in a learning process, the BCM theory predicts increased threshold for subsequent LTP induction and a decreased threshold for LTD induction. Hamada et al. (2008) tested this theory by examining the effects of a priming QPS protocol. The results showed that priming QPS with no after-effect by itself, shifted the threshold for the subsequent LTP/LTD. A priming QPS train at ISI of 5 ms increased the threshold for LTP and decreased the threshold for LTD, while that priming QPS at ISI of 50 ms had the opposite effect. Priming QPS may mimic a learning process that modifies postsynaptic activity and changes the sign of subsequent QPS-induced plasticity. Another important finding of Hamada et al. (2008) is that the first part of the rTMS may have a priming effect on the subsequent part of the rTMS. QPS at 5 ms ISI for 30 min increased cortical excitability but the same stimulation for 40 min had no effect, which may be explained by a priming effect of the first part of the stimulation leading to increased threshold for LTP. Therefore, the duration of stimulation may have a complex effect on the after-effects of rTMS, as any rTMS parameters may be regarded as a priming protocol followed by a subsequent protocol. While frequency (or ISI), stimulus intensity and ITI (mainly for safety reasons) are the main factors that determine the effects of regular rTMS, Hamada et al. (2008) and other recent studies show that pattern (e.g. IBI) and duration of stimulation have complex effects and are important factors to consider when designing rTMS parameters in physiological research or clinical studies.

Neuregulin blocks synaptic strengthening after epileptiform activity in the rat hippocampus

Synaptic strengthening produced by epileptiform activity may contribute to seizure progression and cognitive impairment in epilepsy. Agents that limit this form of plasticity may have therapeutic benefit. Neuregulin is an endogenous growth factor that is released at synapses in an activity dependent manner and can suppress long term potentiation (LTP). Alterations in neuregulin signaling have been associated with schizophrenia. A role for neuregulin in epilepsy has not been explored. We used field potential recordings to examine the role of neuregulin in regulating synaptic strengthening following epileptiform activity in hippocampal slices. Neuregulin had no effect on basal synaptic transmission, isolated NMDA field potentials or GABAergic inhibition on CA1 pyramidal neurons. However, it reversed LTP at CA1 synapses. Brief exposure to 10 mM potassium chloride produced epileptiform bursting and potentiation of CA1 synapses and suppressed the subsequent induction of LTP. Neuregulin reversed high K +-induced synaptic strengthening, enabling LTP induction after neuregulin washout. In this manner neuregulin preserved the dynamic range of synaptic responses and plasticity after epileptiform activity. These results indicate that LTP and high K +-induced synaptic strengthening share a common neuregulin-sensitive mechanism. By opposing synaptic strengthening caused by epileptiform activity, we suggest that neuregulin may reduce the generation and spread of seizures as well as memory deficits associated with epilepsy.

Ongoing in Vivo Experience Triggers Synaptic Metaplasticity in the Neocortex

In vivo experience can occlude subsequent induction of long-term potentiation and enhance long-term depression of synaptic responses. Although a reduced capacity for synaptic strengthening may function to prevent excessive excitation, such an effect paradoxically implies that continued experience or training should not improve and may even degrade neural representations. In mice, we examined the effect of ongoing whisker stimulation on synaptic strengthening at layer 4-2/3 synapses in the barrel cortex. Although N-methyl-d-aspartate receptors were required to initiate strengthening, they subsequently suppressed further potentiation at these synapses in vitro and in vivo. Despite this transition, synaptic strengthening continued with additional sensory activity but instead required the activation of metabotropic glutamate receptors, suggesting a mechanism by which continued experience can result in increasing synaptic strength over time.