Short-term Plastic Changes Research Articles

P208 The effects of transcutaneous spinal cord stimulation on spinal reciprocal inhibition in healthy persons

Introduction Transcutaneous spinal cord stimulation (tSCS) is a non-invasive method to stimulate afferent structures of the spinal neural circuits related with lower limb motor control. Its application is known to improve lower limb motor function in individuals with spinal cord injury. However, it remains unknown whether tSCS induces spinal plasticity, which has an essential role in functional recovery of the lower limb after spinal cord injury and stroke. Objectives The purpose of this study was to investigate the effects of tSCS on spinal reciprocal inhibition in healthy individuals. Methods Twelve healthy volunteers participated in this single-masked, sham-controlled crossover study. The following three paradigms were randomly applied to them on three different days: (1) tSCS; (2) sham tSCS; (3) transcutaneous peripheral nerve patterned electrical stimulation (tPES). tSCS and tPES consisted of a train of 10 pulses at 100 Hz every 2 s for 20 min. tSCS was delivered to the thoracic spine level (Th11/12) with the intensity of sensory threshold × 2.0 without muscle contraction. tPES was applied to common peroneal nerve using the intensity equal to the motor threshold of tibialis anterior muscle. For sham stimulation, the same procedure was used, but the current was delivered for only 30 s.We assessed disynaptic reciprocal inhibition (RI) and presynaptic inhibition (D1) using a soleus H-reflex conditioning-test paradigm. The magnitudes of inhibition was assessed before, immediately after, 15 min and 30 min after the stimulation. Results tSCS significantly increased the amount of D1 inhibition immediately after and at 15 min after when compared with the baseline, and the effects were greater than other conditions immediately after and at 15 min after the stimulation. tSCS concurrently increased the amount of RI immediately after. tPES significantly increased the amount of RI until 15 min after the stimulation, but did not affect the D1 inhibition. Conclusion The present results provide further evidence that tSCS can induce short-term plastic changes in human spinal reciprocal inhibitory interneuron.

Empowering Reentrant Projections from V5 to V1 Boosts Sensitivity to Motion

Evidence from macaques [1] and humans [2, 3] has shown that back projections from extrastriate areas to the primary visual area (V1) determine whether visual awareness will arise. For example, reentrant projections from the visual motion area (V5) to V1 are considered to be critical for awareness of motion [2, 3]. If these projections are also instrumental to functional processing of moving stimuli [4-8], then increasing synaptic efficacy in V5-V1 connections should induce functionally relevant short-term plastic changes, resulting in enhanced perception of visual motion. Using transcranial magnetic stimulation (TMS), we applied a novel cortico-cortical paired associative stimulation (ccPAS) protocol to transiently enhance visual motion sensitivity and demonstrate both the functional relevance of V5-V1 reentrant projections to motion perception and their plasticity. Specifically, we found that ccPAS aimed at strengthening reentrant connectivity from V5 to V1 (but not in the opposite direction) enhanced the human ability to perceive coherent visual motion. This perceptual enhancement followed the temporal profile of Hebbian plasticity [9-18] and was observed only when an optimal timing of 20ms between TMS pulses [2, 3, 5, 6] was used, not when TMS pulses were delivered synchronously. Thus, plastic change is critically dependent on both the direction and timing of connectivity; if either of these requirements was not met, perceptual enhancement did not take place. We therefore provide novel causal evidence that V5-V1 back projections, instrumental to motion perception, are functionally malleable. These findings have implications for theoretical models of visual awareness and for the rehabilitation of visual deficits.

Short-Term Plasticity in Auditory Cortical Circuit Evoked by Monetary Incentive Delay Task

To choose optimally, people must consider both the potential value and the probability of a desired outcome. This idea is reflected in the expected value theory, which considers both the potential value of different courses of action and the probability that each action will lead to a desired outcome. Accordingly, during decision-making people choose an alternative with the highest expected value. The dominant neurobiological models of decision-making assume that the sensory inputs to the decision-making neural networks are stationary. However, many cognitive studies have demonstrated experience-induced plasticity in the primary sensory cortex, suggesting that repeated decisions could modulate the sensory processing. We investigated experience-induced plastic changes in the neural representation of the acoustic cues coding different expected values using a repeated monetary incentive delay task (MID-task; Knutson et al., 2005). Subjects participated in two extensive sessions of an audio-version of the MID-task. Next, we investigated electrophysiological correlates of the experience-induced plasticity of the primary auditory cortex by comparing the mismatch negativity (MMN) component before and after the MID-task sessions. We found that after extensive MID-task training, the stimuli with largest expected value evoked larger MMN responses (as compared to the baseline oddball session) that probably reflects a more fine-grained stimulus discrimination of highly valued stimuli. After extensive MID-task training acoustic cues coding intermediate expected values evoked larger P3a component (as compared to the baseline oddball session), that can indicate a stronger involuntary attention switching toward moderately valued stimuli. Overall, our results show that continuing valuation during the MID-task evokes a short-term plastic changes in the auditory cortices associated with the improved stimulus discrimination and the involuntary attention towards auditory cues with the high expected value.

The synaptic basis of disease

The synaptic basis of disease

Temporal Rearrangement of Pre-ictal PTZ Induced Spike Discharges by Low Frequency Electrical Stimulation to the Amygdaloid Complex

BackgroundEpilepsy is a common neurological disease affecting over 40 million people worldwide. The foremost important challenge of epileptologists has been to control and predict the recurrent and spontaneous seizures of epileptic patients. The application of low frequency electrical stimulation (LFS) in deep brain structures has shown promising results in seizure control. However, the use of LFS as a probing strategy for seizure prediction, thus contributing to a closed loop solution, is still poorly explored. ObjectiveTo improve seizure prediction by producing gradually increasing phase-locked pre-ictal electrographical responses, due to the short-term plastic changes in epileptogenic neural networks, thus behaving as a “programmed” surrogate marker. MethodsUrethane anesthetized rats were divided into 3 groups: the PTZ-noES group was injected with pentylenetetrazole (PTZ 4 mg/ml/min flow rate) i.v. without electrical stimulation (ES); the ES-noPTZ group received ES (0.5 Hz, 0.1 ms pulse width and 0.6 mA) to the amygdaloid complex and the PTZ + ES group received simultaneously i.v. PTZ infusion and ES. After each condition, electrographical parameters and c-Fos expression of regions of interest were evaluated. ResultsAlthough the PTZ + ES group had no evident change in the sustained electrographic seizure onset, duration and/or frequency spectrum; c-Fos labeling showed a different expression pattern when compared to the PTZ-noES and ES-noPTZ. Also, PTZ + ES formed a gradually increasing evoked potential; confirming the strong coupling of reverberant neural networks induced by ES – phase locked to stimuli. ConclusionES induces a detectable temporal rearrangement of pre-ictal activity, which has suggestive applicability to seizure prediction.

Central common drive to antagonistic ankle muscles in relation to short-term cocontraction training in nondancers and professional ballet dancers

Optimization of cocontraction of antagonistic muscles around the ankle joint has been shown to involve plastic changes in spinal and cortical neural circuitries. Such changes may explain the ability of elite ballet dancers to maintain a steady balance during various ballet postures. Here we investigated whether short-term cocontraction training in ballet dancers and nondancers leads to changes in the coupling between antagonistic ankle motor units. Eleven ballet dancers and 10 nondancers were recruited for the study. Prior to training, ballet dancers and nondancers showed an equal amount of coherence in the 15- to 35-Hz frequency band and short-term synchronization between antagonistic tibialis anterior and soleus motor units. The ballet dancers tended to be better at maintaining a stable cocontraction of the antagonistic muscles, but this difference was not significant (P = 0.09). Following 27 min of cocontraction training, the nondancers improved their performance significantly, whereas no significant improvement was observed for the ballet dancers. The nondancers showed a significant increase in 15- to 35-Hz coherence following the training, whereas the ballet dancers did not show a significant change. A group of control subjects (n = 4), who performed cocontraction of the antagonistic muscles for an equal amount of time, but without any requirement to improve their performance, showed no change in coherence. We suggest that improved ability to maintain a stable cocontraction around the ankle joint is accompanied by short-term plastic changes in the neural drive to the involved muscles, but that such changes are not necessary for maintained high-level performance.

Benthic disturbance affects intertidal food web dynamics: implications for investigations of ecosystem functioning

MEPS Marine Ecology Progress Series Contact the journal Facebook Twitter RSS Mailing List Subscribe to our mailing list via Mailchimp HomeLatest VolumeAbout the JournalEditorsTheme Sections MEPS 466:35-41 (2012) - DOI: https://doi.org/10.3354/meps09938 Benthic disturbance affects intertidal food web dynamics: implications for investigations of ecosystem functioning Christopher P. Cesar1,2,*, Chris L. J. Frid1 1School of Environmental Sciences, University of Liverpool, Brownlow Street, Liverpool L69 3GP, UK 2Present address: APEM, Riverview, A17 Embankment Business Park, Heaton Mersey, Stockport SK4 3GN, UK *Email: christopher_p_cesar@yahoo.co.uk ABSTRACT: Analysis of biological traits within assemblages is increasingly used as a proxy for ecological functioning. However, taxa often show plasticity in the expression of traits and can potentially change trait expression depending on local conditions. While many forms of disturbance will lead to changes in the species composition of the assemblage, small-scale disturbances can trigger alterations in the behaviour of taxa and hence the ecological roles they are delivering. Such changes would not be detected by biological traits analysis (BTA) alone. BTA therefore has the potential to misinform as to the contribution of assemblages to ecological processes. To assess the potential for taxa to change their expression of traits, the feeding modes of 8 taxa from 2 intertidal assemblages in north-west England, UK, were investigated using stable isotope analyses following experimental sediment disturbance and removal of cockles Cerastoderma edule. Two of the 8 taxa exhibited significant changes to their isotopic composition within disturbed plots. Short-term plastic changes to food web dynamics following changes in environmental conditions have implications for the suitability of BTA as a tool for investigating ecosystem function. Although BTA provides much insight into the ecological roles of taxa within systems and can be extremely effective at identifying changes associated with different assemblage compositions, it is conceivable that changes to ecological functioning may be undetected by BTA alone, and hence there is the need for this approach to be supported by experimental observation. KEY WORDS: Trait plasticity · Ecosystem function · Anthropogenic impact · Biological traits analysis · BTA Full text in pdf format PreviousNextCite this article as: Cesar CP, Frid CLJ (2012) Benthic disturbance affects intertidal food web dynamics: implications for investigations of ecosystem functioning. Mar Ecol Prog Ser 466:35-41. https://doi.org/10.3354/meps09938 Export citation RSS - Facebook - Tweet - linkedIn Cited by Published in MEPS Vol. 466. Online publication date: October 15, 2012 Print ISSN: 0171-8630; Online ISSN: 1616-1599 Copyright © 2012 Inter-Research.

Compensatory Plasticity in the Action Observation Network: Virtual Lesions of STS Enhance Anticipatory Simulation of Seen Actions

Observation of snapshots depicting ongoing motor acts increases corticospinal motor excitability. Such motor facilitation indexes the anticipatory simulation of observed (implied) actions and likely reflects computations occurring in the parietofrontal nodes of a cortical network subserving action perception (action observation network, AON). However, direct evidence for the active role of AON in simulating the future of seen actions is lacking. Using a perturb-and-measure transcranial magnetic stimulation (TMS) approach, we show that off-line TMS disruption of regions within (inferior frontal cortex, IFC) and upstream (superior temporal sulcus, STS) the parietofrontal AON transiently abolishes and enhances the motor facilitation to observed implied actions, respectively. Our findings highlight the critical role of IFC in anticipatory motor simulation. More importantly, they show that disruption of STS calls into play compensatory motor simulation activity, fundamental for counteracting the noisy visual processing induced by TMS. Thus, short-term plastic changes in the AON allow motor simulation to deal with any gap or ambiguity of ever-changing perceptual worlds. These findings support the active, compensatory, and predictive role of frontoparietal nodes of the AON in the perception and anticipatory simulation of implied actions.

Word position affects stimulus recognition: Evidence for early ERP short-term plastic modulation

The present study was aimed at investigating the short-term plastic changes that follow word learning at a neurophysiological level. The main hypothesis was that word position (left or right visual field, LVF/RH or RVF/LH) in the initial learning phase would leave a trace that affected, in the subsequent recognition phase, the Recognition Potential (i.e., the first negative component distinguishing words from other stimuli) elicited 220–240 ms after centrally presented stimuli. Forty-eight students were administered, in the learning phase, 125 words for 4 s, randomly presented half in the left and half in the right visual field. In the recognition phase, participants were split into two equal groups, one was assigned to the Word task, the other to the Picture task (in which half of the 125 pictures were new, and half matched prior studied words). During the Word task, old RVF/LH words elicited significantly greater negativity in left posterior sites with respect to old LVF/RH words, which in turn showed the same pattern of activation evoked by new words. Therefore, correspondence between stimulus spatial position and hemisphere specialized in automatic word recognition created a robust prime for subsequent recognition. During the Picture task, pictures matching old RVF/LH words showed no differences compared with new pictures, but evoked significantly greater negativity than pictures matching old LVF/RH words. Thus, the priming effect vanished when the task required a switch from visual analysis to stored linguistic information, whereas the lack of correspondence between stimulus position and network specialized in automatic word recognition (i.e., when words were presented to the LVF/RH) revealed the implicit costs for recognition. Results support the view that short-term plastic changes occurring in a linguistic learning task interact with both stimulus position and modality (written word vs. picture representation).

Impaired Visual Hand Recognition in Preoperative Patients during Brachial Plexus Anesthesia

Perceptual illusions described in healthy subjects undergoing regional anesthesia (RA) are probably related to short-term plastic brain changes. We addressed whether performance on an implicit mental rotation task reflects these RA-induced changes in body schema brain representations. Studying these changes in healthy volunteers may shed light on normal function and the central mechanisms of pain. Performance pattern was studied in upper limb-anesthetized subjects on a left/right hand judgment task, which is known to involve motor imagery processes relating to hand posture. Three conditions were used: control (i.e., absence of deafferentation), RA (i.e., deafferentation), and vision (i.e., deafferentated limb exposed to view). To limit potential bias such as order effect, the control state was recorded in a randomized manner. All subjects described perceptual illusions of their anesthetized limb. They were slower and less accurate on the task during RA compared with control. Response patterns were similar in all conditions, suggesting sensitivity of performance to arm/hand biomechanical constraints. Vision was associated with an increase in the proportion of correct responses and a reduction of the response times in hand judgment and was accompanied by disappearance of the lateralization of the underlying mental representations, which was identified during RA. These results suggest the following: (1) the right/left judgment task involves mental simulation of hand movements, (2) underlying mental representations and their neural substrates are subject to acute alterations after RA, and (3) the proprioceptive deficit induced by RA is influenced by the subject's ability to see the anesthetized limb.

In search of augmentation at human SI: Somatosensory cortical responses to stimulus trains and their modulation by motor activity

In many animal preparations, repeated stimulation at ca. 10 Hz in thalamic nuclei leads to rapid changes in the cortical evoked responses, known as the augmenting response. The present study was undertaken to evaluate whether anything similar to the augmenting response can be observed in awake human subjects when a peripheral nerve is stimulated, and whether a possible human correlate of augmenting would be modified when the subject is engaged in an active motor task. Somatosensory-evoked magnetic fields (SEFs) were recorded in healthy human subjects in response to stimulus trains (15 pulses at 10 Hz) applied to the left median nerve. SEFs were recorded in a resting condition and during a finger-tapping task performed with the stimulated hand. In the resting condition, the most marked change in the SEF configuration was a reduction of the P35m deflection and a concurrent enhancement of the N45m deflection during the 1st few stimuli of the trains. Another conspicuous feature was a prolongation of the latencies of the N45m and P60m deflections toward the end of the train. In the motor task, the response modulation during the pulse trains was in general similar to the resting condition. The most notable difference was that the P35m amplitude was markedly reduced already for the 1st pulse of the train when compared with rest. Also, the latencies of N45m and P60m were not prolonged during the train. We discuss the possibility that the reduction of P35m and a concurrent increase of N45m during a pulse train constitute a human analogue to the augmenting response, and suggest that these changes may reflect a decrease of inhibitory postsynaptic potentials (IPSPs, P35m) and an increase of secondary excitatory postsynaptic potentials (N45m) during stimulus train presentation. The reduction of P35m during motor activity compared with rest already at the beginning of stimulus trains suggests that postsynaptic IPSPs in response to afferent stimulation are reduced during active movement. Otherwise the short-term plastic changes were similar during rest and motor activity. Finally, the results suggest slowing down of intracortical network processing with repeated stimulation, and that this slowing is not present during an active motor task which depends on afferent feedback information.

Brain‐derived neurotrophic factor and risk for primary adult‐onset cranial‐cervical dystonia

Adult-onset dystonia may be related, amongst other factors, to abnormal neuronal plasticity in cortical and subcortical structures. Brain-derived neurotrophic factor is a major modulator of synaptic efficiency and neuronal plasticity. Recent works documented that a single nucleotide polymorphism (SNP) of the BDNF gene, the Val66Met SNP, modulates short-term plastic changes within motor cortical circuits. In this study we aimed at exploring the effect of this SNP upon the risk of developing common forms of primary adult-onset dystonia. We explored the influence of the Val66Met SNP of the BDNF gene on the risk of cranial and cervical dystonia in a cohort of 156 Italian patients and 170 age- and gender-matched healthy control subjects drawn from the same population. The presence of the rare Met allele was not significantly associated with the diagnosis of dystonia (age- and gender-adjusted odds ratios of 1.22, P = 0.38). The study had a >90% power to detect a 50% change in the risk of developing cranial-cervical dystonia associated with the presence of the Met allele. Moreover, there was no relationship between Val66Met SNP and age at dystonia onset or type of dystonia. Our data do not support the common variant Val66Met of the BDNF gene as an etiologic factor shared by the various forms of primary adult-onset dystonia.

Cortical and Spinal Excitability Changes After Robotic Gait Training in Healthy Participants

Background. Recent studies have proposed a role for robotic gait training in participants with acquired brain injury, but the effects on the excitability of cortical and spinal neurons even in healthy participants are uncertain. Objective. To investigate changes in corticospinal excitability in healthy participants after active and passive robotic gait training in a driven gait orthosis (DGO), the Lokomat. Methods. Thirteen healthy participants took part in 2 experiments. Each participant performed 20 minutes of active and passive gait training in a DGO. Motor evoked potentials (MEP), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), F-wave frequency, and Mmax were measured in the right tibialis anterior muscle before and after training. Results. Active training led to a decline in MEP amplitude and F-wave frequency. The MEP decline was associated with subjective muscle fatigue. Passive training induced a decrease in SICI lasting for 20 minutes after training. Conclusions. The decline in MEP after active training is most likely because of central fatigue, whereas the decreased F-wave frequency might represent short-term plastic changes in the spinal cord. The decrease in SICI after passive training probably reflects a decrease in intracortical GABA activity, which could benefit the acquisition of new motor skills.

Some implications of the short-term synaptic plasticity for neuronal computation: a model study

Spikes arriving at the synaptic connection produce short-term plastic changes of the synaptic efficacy. Model experiments have shown that paired-pulse facilitation attaining its maximum after a specific interval between a pair of arriving spikes might turn a “weak” plastic synapse attached to an integrate-and-fire neuron to a frequency-tuned device. Resulting computational capabilities create biologically plausible mechanisms of information processing relating to: (i) real-time identification of temporal patterns in a stream of random spiking activity (a recognition problem); and (ii) codetermination of the specific activity routing among neurons (an addressing problem) resulting in definite spatio-temporal patterns of the output activity (an input-output pattern problem).

The subiculum to entorhinal cortex projection is capable of sustaining both short- and long-term plastic changes

The hippocampus communicates with the neocortex via the entorhinal cortex. These areas are thought to be critically involved in the consolidation of memories. The hippocampus is considered to be the site of association of sensory information, which is then laid down for long-term storage in the neocortex. We examined the projection from the subiculum to the entorhinal cortex to determine whether it could function to transfer this hippocampally-processed information to the neocortex. Following stimulation in the subiculum we demonstrate a negative-going deflection followed by a positive-going deflection in the entorhinal cortex. This projection is capable of short-term plastic changes in the form of PPF. FIn addition, we demonstrate that long-term synaptic changes in the form of LTP and LTD could be sustained for at least 30 min on this pathway. Finally we show that PPF changes after LTP and LTD, suggesting that a presynaptic mechanism may be involved in both of these pathways.

Rapid Plastic Changes of Human Primary Motor Cortex with Repetitive Motor Practice and Transcranial Magnetic Stimulation

Excitability changes of human primary motor cortex are assumed to be associated with motor learning processes. To examine motor behavioral and neural mechanisms in these processes, the adaptive motor learning processes of the index finger abduction were investigated using motor evoked potential (MEP) elicited from the first dorsal interosseous and extensor carpi radialis muscles. Practice effects were examined on changes of MEP amplitudes elicited from these muscles during motor imagery. Given general consensus that the MEP amplitude change during motor imagery is a useful parameter reflecting changes in excitability of the human primary motor cortex, the present results, that MEP amplitudes of both muscles increased with repeated practice by the index finger abduction and that magnitudes of MEP amplitudes of both muscles (motor learning curves) were clearly different, suggested that participation of the muscles performing the index finger abduction gradually changed with practice. Short-term plastic changes of human primary motor cortex occur with repetitive practice and such adaptive change in human primary motor cortex is expressed in human voluntary movement that becomes more automatic.

The NMDA antagonist memantine affects training induced motor cortex plasticity – a study using transcranial magnetic stimulation [ISRCTN65784760

BackgroundTraining of a repetitive synchronised movement of two limb muscles leads to short-term plastic changes in the primary motor cortex, which can be assessed by transcranial magnetic stimulation (TMS) mapping. We used this paradigm to study the effect of memantine, a NDMA antagonist, on short-term motor cortex plasticity in 20 healthy human subjects, and we were especially interested in possible differential effects of different treatment regimens. In a randomised double-blinded cross over study design we therefore administered placebo or memantine either as a single dosage or as an ascending dosage over 8 days. Before and after one hour of motor training, which consisted of a repetitive co-contraction of the abductor pollicis brevis (APB) and the deltoid muscle, we assessed the motor output map of the APB muscle by TMS under the different conditions.ResultsWe found a significant medial shift of the APB motor output map after training in the placebo condition, indicating training-induced short-term plastic changes in the motor cortex. A single dosage of memantine had no significant effect on this training-induced plasticity, whereas memantine administered in an ascending dosage over 8 days was able to block the cortical effect of the motor training. The memantine serum levels after 8 days were markedly higher than the serum levels after a single dosage of memantine, but there was no individual correlation between the shift of the motor output map and the memantine serum level. Besides, repeated administration of a low memantine dosage also led to an effective blockade of training-induced cortical plasticity in spite of serum levels comparable to those reached after single dose administration, suggesting that the repeated administration was more important for the blocking effect than the memantine serum levels.ConclusionWe conclude that the NMDA-antagonist memantine is able to block training-induced motor cortex plasticity when administered over 8 days, but not after administration of a single dose. This differential effect might be mainly due to the prolonged action of memantine at the NMDA receptor. These findings must be considered if clinical studies are designed, which aim at evaluating the potency of memantine to prevent "maladaptive" plasticity, e.g. after limb amputation.

Rapid change of tonotopic maps in the human auditory cortex during pitch discrimination

Objective To study early cognitive processes and hemispheric differences in the primary auditory cortex during selective attention. Methods We measured auditory evoked magnetic fields (AEFs) to 400 and 4000 Hz tone pips that were randomly presented at the right or left ear. Subjects paid attention to target stimuli during pitch (high or low) or laterality (left or right) discrimination tasks. In the control session, 400 or 4000 Hz tone alone was presented at the left or right ear. We calculated the location and strength of N100m dipole for 400 and 4000 Hz tones, based on the AEFs obtained from the hemisphere contralateral to the stimulated ear. Results N100m amplitude increased in both hemispheres in pitch or laterality discriminating conditions. N100m latency also shortened during selective attention. The N100m dipole distance between 400 and 4000 Hz tones was enlarged, especially in the right auditory cortex during pitch discrimination task, but was unchanged during the laterality discrimination task. Conclusions We conclude that these dynamic changes in the N100m dipole reflect short-term plastic changes in the primary auditory cortex, supporting early selection models. Significance This work is the first to disclose short-term plastic changes during pitch discrimination in the human auditory cortex based on the analysis of magnetoencephalography.

ERK Signaling Translates to New Memories

Memory consolidation and the enduring changes in synaptic function that may underlie long-lasting memories both depend on synthesis of new mRNA and protein. The mechanisms by which synaptic activity affects transcription have been intensively explored, whereas the route to translational regulation is poorly understood. Kelleher et al. used cultured neurons and a mouse mutant to explore the involvement of the extracellular signal-regulated kinase (ERK) mitogen-associated protein kinase (MAPK) signaling pathway--which has been implicated in synaptic plasticity, learning, and memory--in stimulus-dependent translation. In primary hippocampal neurons, pharmacological analysis indicated that stimulus-dependent activation of a translational reporter and pulse labeling of endogenous transcripts depended on ERK signaling, as did phosphorylation of ribosomal protein S6 and the translation factors eIF4E and 4E-BP1. Transgenic mice expressing a dominant-negative form of the ERK kinase MAPK-extracellular signal regulated kinase-1 (dnMEK1) in postnatal forebrain exhibited impaired spatial reference memory and long-term contextual fear conditioning. Although basal hippocampal synaptic transmission, short-term plastic changes, and an early phase of long-term potentiation (LTP) appeared normal, pharmacological and kinetic analysis of late LTP (L-LTP, which depends on protein synthesis) suggested a selective deficit in the translational component of this process. Hippocampal slices from dnMEK1 mice showed reduced ERK phosphorylation, incorporation of 35 S-methionine, and phosphorylation of translation factors in response to L-LTP-inducing tetanic stimuli. Similarly, hippocampi from dnMEK1 mice showed reduced phosphorylation of ERK and translation factors in response to fear conditioning. Thus regulation of translation through the MAPK signaling pathway appears to play a critical role in long-lasting memory and long-term changes in synaptic function. R. J. Kelleher III, A. Govindarajan, H.-Y. Jung, H. Kang, S. Tonegawa, Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116 , 467-479 (2004). [Online Journal]

Characterization of the anticonvulsant profile and enantioselective pharmacokinetics of the chiral valproylamide propylisopropyl acetamide in rodents

1. Propylisopropyl acetamide (PID) is a new chiral amide derivative of valproic acid. The purpose of this study was to evaluate the anticonvulsant activity of PID in rodent models of partial, secondarily generalized and sound-induced generalized seizures which focus on different methods of seizure induction, both acute stimuli, and following short-term plastic changes as a result of kindling, and to assess enantioselectivity and enantiomer-enantiomer interactions in the pharmacokinetics and pharmacodynamics of racemic PID and its pure enantiomers in rodents. 2. Anticonvulsant activity of (S)-PID, (R)-PID and racemic PID was evaluated in the 6 Hz psychomotor seizure model in mice, in the hippocampal kindled rat, and in the Frings audiogenic seizure susceptible mouse. The pharmacokinetics of (S)-PID and (R)-PID was studied in mice and rats. 3. In mice (S)-PID, (R)-PID and racemic PID were effective in preventing the 6 Hz seizures with (R)-PID being significantly (P < 0.05) more potent (ED(50) values 11 mg kg(-1), 46 mg kg(-1) and 57 mg kg(-1) at stimulation intensities of 22, 32 and 44 mA, respectively) than (S)-PID (ED(50) values 20 mg kg(-1), 73 mg kg(-1) and 81 mg kg(-1) at stimulation intensities of 22, 32 and 44 mA, respectively). (S)-PID, (R)-PID and racemic PID also blocked generalized seizures in the Frings mice (ED(50) values 16 mg kg(-1), 20 mg kg(-1) and 19 mg kg(-1) respectively). 4. In the hippocampal kindled rat a dose of 40 mg kg(-1) of (R)- and (S)-PID prevented the secondarily generalized seizure, whereas racemic PID also blocked the expression of partial seizures following an i.p. dose of 40 mg kg(-1). Racemic PID also significantly increased the seizure threshold in this model. 5. Mechanistic studies showed that PID did not affect voltage-sensitive sodium channels or kainate-, GABA- or NMDA- evoked currents. 6. The pharmacokinetics of PID was enantioselective following i.p. administration of individual enantiomers to mice, with (R)-PID having lower clearance and longer half-life than (S)-PID. In rats and mice, no enantioselectivity in the pharmacokinetics of PID was observed following administration of the racemate, which may be due to enantiomer-enantiomer interaction. 7. This study demonstrated that PID has both enantioselective pharmacokinetics and pharmacodynamics. The better anticonvulsant potency of (R)-PID in comparison to (S)-PID may be due to its more favorable pharmacokinetic profile. The enhanced efficacy of the racemate over the individual enantiomers in the kindled rat may be explained by a pharmacokinetic enantiomer-enantiomer interaction in rats. This study also showed the importance of studying the pharmacokinetics and pharmacodynamics of chiral drugs following administration of the individual enantiomers as well as the racemic mixture.