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Frontiers in Cellular Neuroscience, 17, ISSN:1662-5102

Bayesian Active Learning (BAL) is an efficient framework for learning the parameters of a model, in which input stimuli are selected to maximize the mutual information between the observations and the unknown parameters. However, the applicability of BAL to experiments is limited as it requires performing high-dimensional integrations and optimizations in real time: current methods are either too time consuming, or only applicable to specific models. Here, we propose an Efficient Sampling-Based Bayesian Active Learning (ESB-BAL) framework, which is efficient enough to be used in real-time biological experiments. We apply our method to the problem of estimating the parameters of a chemical synapse from the postsynaptic responses to evoked presynaptic action potentials. Using synthetic data and synaptic whole-cell patch-clamp recordings, we show that our method can improve the precision of model-based inferences, thereby paving the way towards more systematic and efficient experimental designs in physiology., Major review after submission: - Change of title - Add biological recordings

Animal behavior is remarkably robust despite constant changes in neural activity. Homeostatic plasticity stabilizes central nervous system (CNS) function on time scales of hours to days. If and how CNS function is stabilized on more rapid time scales remains unknown. Here, we discovered that mossy fiber synapses in the mouse cerebellum homeostatically control synaptic efficacy within minutes after pharmacological glutamate receptor impairment. This rapid form of homeostatic plasticity is expressed presynaptically. We show that modulations of readily releasable vesicle pool size and release probability normalize synaptic strength in a hierarchical fashion upon acute pharmacological and prolonged genetic receptor perturbation. Presynaptic membrane capacitance measurements directly demonstrate regulation of vesicle pool size upon receptor impairment. Moreover, presynaptic voltage-clamp analysis revealed increased Ca2+-current density under specific experimental conditions. Thus, homeostatic modulation of presynaptic exocytosis through specific mechanisms stabilizes synaptic transmission in a CNS circuit on time scales ranging from minutes to months. Rapid presynaptic homeostatic plasticity may ensure stable neural circuit function in light of rapid activity-dependent plasticity., Proceedings of the National Academy of Sciences of the United States of America, 116 (47), ISSN:0027-8424, ISSN:1091-6490

AMPA receptors (AMPARs) mediate excitatory neurotransmission in the CNS and their subunit composition determines synaptic efficacy. Whereas AMPAR subunits GluA1–GluA3 have been linked to particular forms of synaptic plasticity and learning, the functional role of GluA4 remains elusive. Here we used electrophysiological, computational and behavioral approaches to demonstrate a crucial function of GluA4 for synaptic excitation and associative memory formation in the cerebellum. Notably, GluA4-knockout mice had ∼80% reduced mossy fiber to granule cell synaptic transmission. The fidelity of granule cell spike output was markedly decreased despite attenuated tonic inhibition and increased NMDA receptor-mediated transmission. Computational modeling revealed that GluA4 facilitates pattern separation that is important for associative learning. On a behavioral level, while locomotor coordination was generally spared, GluA4-knockout mice failed to form associative memories during delay eyeblink conditioning. These results demonstrate an essential role for GluA4-containing AMPARs in cerebellar information processing and associative learning.

Cerebellar granule cells (GCs) make up the majority of all neurons in the vertebrate brain, but heterogeneities among GCs and potential functional consequences are poorly understood. Here, we identified unexpected gradients in the biophysical properties of GCs in mice. GCs closer to the white matter (inner-zone GCs) had higher firing thresholds and could sustain firing with larger current inputs than GCs closer to the Purkinje cell layer (outer-zone GCs). Dynamic Clamp experiments showed that inner- and outer-zone GCs preferentially respond to high- and low-frequency mossy fiber inputs, respectively, enabling dispersion of the mossy fiber input into its frequency components as performed by a Fourier transformation. Furthermore, inner-zone GCs have faster axonal conduction velocity and elicit faster synaptic potentials in Purkinje cells. Neuronal network modeling revealed that these gradients improve spike-timing precision of Purkinje cells and decrease the number of GCs required to learn spike-sequences. Thus, our study uncovers biophysical gradients in the cerebellar cortex enabling a Fourier-like transformation of mossy fiber inputs., eLife digest The timing of movements such as posture, balance and speech are coordinated by a region of the brain called the cerebellum. Although this part of the brain is small, it contains a huge number of tiny nerve cells known as granule cells. These cells make up more than half the nerve cells in the human brain. But why there are so many is not well understood. The cerebellum receives signals from sensory organs, such as the ears and eyes, which are passed on as electrical pulses from nerve to nerve until they reach the granule cells. These electrical pulses can have very different repetition rates, ranging from one pulse to a thousand pulses per second. Previous studies have suggested that granule cells are a uniform population that can detect specific patterns within these electrical pulses. However, this would require granule cells to identify patterns in signals that have a range of different repetition rates, which is difficult for individual nerve cells to do. To investigate if granule cells are indeed a uniform population, Straub, Witter, Eshra, Hoidis et al. measured the electrical properties of granule cells from the cerebellum of mice. This revealed that granule cells have different electrical properties depending on how deep they are within the cerebellum. These differences enabled the granule cells to detect sensory signals that had specific repetition rates: signals that contained lots of repeats per second were relayed by granule cells in the lower layers of the cerebellum, while signals that contained fewer repeats were relayed by granule cells in the outer layers. This ability to separate signals based on their rate of repetition is similar to how digital audio files are compressed into an MP3. Computer simulations suggested that having granule cells that can detect specific rates of repetition improves the storage capacity of the brain. These findings further our understanding of how the cerebellum works and the cellular mechanisms that underlie how humans learn and memorize the timing of movement. This mechanism of separating signals to improve storage capacity may apply to other regions of the brain, such as the hippocampus, where differences between nerve cells have also recently been reported.

In the central nervous system, the frequency at which reliable synaptic transmission can be maintained varies strongly between different types of synapses. Several pre- and postsynaptic processes must interact to enable high-frequency synaptic transmission. One of the mechanistically most challenging issues arises during repetitive neurotransmitter release, when synaptic vesicles fuse in rapid sequence with the presynaptic plasma membrane within the active zone (AZ), potentially interfering with the structural integrity of the AZ itself. Here we summarize potential mechanisms that help to maintain AZ integrity, including arrangement and mobility of release sites, calcium channel mobility, as well as release site clearance via lateral diffusion of vesicular proteins and via endocytotic membrane retrieval. We discuss how different types of synapses use these strategies to maintain high-frequency synaptic transmission.

Cerebellar granule cells (GCs) making up majority of all the neurons in the vertebrate brain, but heterogeneities among GCs and potential functional consequences are poorly understood. Here, we identified unexpected gradients in the biophysical properties of GCs. GCs closer to the white matter (inner-zone GCs) had higher firing thresholds and could sustain firing with larger current inputs. Dynamic clamp experiments showed that inner- and outer-zone GCs preferentially respond to high- and low-frequency mossy fiber inputs, respectively, enabling to disperse the mossy fiber input into its frequency components as performed by a Fourier transformation. Furthermore, inner-zone GCs have faster axonal conduction velocity and elicit faster synaptic potentials in Purkinje cells. Neuronal network modeling revealed that these gradients improve spike-timing precision of Purkinje cells and decrease the number of GCs required to learn spike-sequences. Thus, our study uncovers biophysical gradients in the cerebellar cortex enabling a Fourier-like transformation of mossy fiber inputs.

Plastic changes in synaptic transmission are thought to underlie learning and memory formation. However, changes in synaptic function are only meaningful in the context of stable baseline function. Accumulating evidence suggests that homeostatic signaling systems actively stabilize synaptic transmission in response to neural activity perturbation. Homeostatic mechanisms control both presynaptic and postsynaptic function. Here, we review recent advances in the field of presynaptic homeostatic plasticity (PHP). We discuss PHP in the context of basic mechanisms controlling neurotransmitter release, highlight emerging similarities between different synapses in different species, and summarize new insights into the molecular mechanisms underlying this evolutionary conserved form of synaptic plasticity.

The fusion of neurotransmitter-filled vesicles during synaptic transmission is balanced by endocytotic membrane retrieval. Despite extensive research, the speed and mechanisms of synaptic vesicle endocytosis have remained controversial. Here, we establish low-noise time-resolved membrane capacitance measurements that allow monitoring changes in surface membrane area elicited by single action potentials and stronger stimuli with high-temporal resolution at physiological temperature in individual bona-fide mature central synapses. We show that single action potentials trigger very rapid endocytosis, retrieving presynaptic membrane with a time constant of 470 ms. This fast endocytosis is independent of clathrin but mediated by dynamin and actin. In contrast, stronger stimuli evoke a slower mode of endocytosis that is clathrin, dynamin, and actin dependent. Furthermore, the speed of endocytosis is highly temperature dependent with a Q10 of ∼3.5. These results demonstrate that distinct molecular modes of endocytosis with markedly different kinetics operate at central synapses.

Fast synchronous neurotransmitter release at the presynaptic active zone is triggered by local Ca(2+) signals, which are confined in their spatiotemporal extent by endogenous Ca(2+) buffers. However, it remains elusive how rapid and reliable Ca(2+) signaling can be sustained during repetitive release. Here, we established quantitative two-photon Ca(2+) imaging in cerebellar mossy fiber boutons, which fire at exceptionally high rates. We show that endogenous fixed buffers have a surprisingly low Ca(2+)-binding ratio (∼ 15) and low affinity, whereas mobile buffers have high affinity. Experimentally constrained modeling revealed that the low endogenous buffering promotes fast clearance of Ca(2+) from the active zone during repetitive firing. Measuring Ca(2+) signals at different distances from active zones with ultra-high-resolution confirmed our model predictions. Our results lead to the concept that reduced Ca(2+) buffering enables fast active zone Ca(2+) signaling, suggesting that the strength of endogenous Ca(2+) buffering limits the rate of synchronous synaptic transmission.

Here we explore the relationship between presynaptic homeostatic plasticity and proteasome function at the Drosophila neuromuscular junction. First, we demonstrate that the induction of homeostatic plasticity is blocked after presynaptic proteasome perturbation. Proteasome inhibition potentiates release under baseline conditions but not during homeostatic plasticity, suggesting that proteasomal degradation and homeostatic plasticity modulate a common pool of vesicles. The vesicles that are regulated by proteasome function and recruited during homeostatic plasticity are highly EGTA sensitive, implying looser Ca2+ influx-release coupling. Similar to homeostatic plasticity, proteasome perturbation enhances presynaptic Ca2+ influx, readily-releasable vesicle pool size, and does not potentiate release after loss of specific homeostatic plasticity genes, including the schizophrenia-susceptibility gene dysbindin. Finally, we provide genetic evidence that Dysbindin levels regulate the access to EGTA-sensitive vesicles. Together, our data suggest that presynaptic protein degradation opposes the release of low-release probability vesicles that are potentiated during homeostatic plasticity and whose access is controlled by dysbindin., At the fly neuromuscular junction, postsynaptic receptor perturbation induces homeostatic enhancement of neurotransmitter release. Here, the authors show that the presynaptic proteasome controls a vesicle pool required for homeostatic plasticity and that dysbindin is required to access this pool.

Over a century ago, the Spanish anatomist Ramon y Cajal described ‘mossy fibres’ in the hippocampus and the cerebellum, which contain several presynaptic boutons. Technical improvements in recent decades have allowed direct patch-clamp recordings from both hippocampal and cerebellar mossy fibre boutons (hMFBs and cMFBs, respectively), making them ideal models to study fundamental properties of synaptic transmission. hMFBs and cMFBs have similar size and shape, but each hMFB contacts one postsynaptic hippocampal CA3 pyramidal neuron, while each cMFB contacts ∼50 cerebellar granule cells. Furthermore, hMFBs and cMFBs differ in terms of their functional specialization. At hMFBs, a large number of release-ready vesicles and low release probability (

The speed of neuronal information processing depends on neuronal firing frequency. Here, we describe the evolutionary advantages and ubiquitous occurrence of high-frequency firing within the mammalian nervous system in general. The highest firing frequencies so far have been observed at the cerebellar mossy fiber to granule cell synapse. The mechanisms enabling high-frequency transmission at this synapse are reviewed and compared with other synapses. Finally, information coding of high-frequency signals at the mossy fiber synapse is discussed. The exceptionally high firing frequencies and amenability to high-resolution technical approaches both in vitro and in vivo establish the cerebellar mossy fiber synapse as an attractive model to investigate high-frequency signaling from the molecular up to the network level.

Die Funktion unseres Zentralnervensystems beruht auf der zeitlich präzisen Übertragung elektrischer Signale zwischen Neuronen. Diese synaptische Übertragung findet in weniger als einer tausendstel Sekunde statt. Eine schnelle und hochfrequente Signalübertragung erweitert die Kodierungskapazität und beschleunigt die Verarbeitung von Informationen. Obwohl viele der an synaptischer Übertragung beteiligten Prozesse und Proteine bekannt sind, ist das Verständnis der Mechanismen, die für eine schnelle und hochfrequente Signalübertragung verantwortlich sind, bisher unvollständig. Um die Mechanismen hochfrequenter synaptischer Übertragung zu untersuchen, wurden in dieser Arbeit prä- und postsynaptische Patch-Clamp Ableitungen an der zerebellären Moosfaser-Körnerzell-Synapse in akuten Hirnschnitten der Maus eingesetzt. Es zeigte sich, dass diese Synapse präsynaptische Aktionspotenziale mit einer Frequenz über einem Kilohertz feuern kann und dass Informationen in diesem Frequenzbereich an die postsynaptische Zelle übertragen werden können. Hierbei vermitteln besonders schnelle Natrium- und Kalium-Kanäle eine extrem kurze Dauer der Aktionspotenziale, die dennoch metabolisch relativ effizient sind. Schnelle Kalzium-Kanäle und eine schwache präsynaptische Kalzium-Pufferung ermöglichen eine synchrone Vesikelfreisetzung mit hohen Frequenzen. Zusätzlich greift die Präsynapse auf einen großen Vorrat an freisetzbaren Vesikeln zurück, dessen Auffüllung besonders schnell stattfindet. Aufgrund der hochfrequenten synaptischen Übertragung ist die Moosfaser- Körnerzell-Synapse ideal, um zu untersuchen, wie schnell die auf eine Vesikelfreisetzung folgende Endozytose vonstatten geht. Mit optimierten, hochauflösenden Kapazitätsmessungen konnte an der Moosfaser-Körnerzell- Synapse eine sehr schnelle Endozytose nach einzelnen Aktionspotenzialen gezeigt werden. Die hohe Geschwindigkeit der Endozytose unterstützt somit eine hochfrequente synaptische Übertragung. Diese schnelle Endozytose wird durch die Moleküle Dynamin und Actin vermittelt und ist unabhängig von einer Wirkung von Clathrin. Stärkere Stimuli wie längere Depolarisationen evozieren eine langsamere Form der Endozytose, die zusätzlich Clathrin-abhängig ist. Durch die mechanistische Beschreibung hochfrequenter Signalübertragung an einer zentralen Synapse erweitern die Ergebnisse der vorliegenden Arbeit unser Verständnis von synaptischer Übertragung und Informationsverarbeitung im Zentralnervensystem.

Aim We aimed to investigate the induction of long-term potentiation (LTP)-like plasticity by paired associative stimulation (PAS) in patients with high-functioning autism and Asperger syndrome (HFA/AS). Method PAS with an interstimulus interval between electrical and transcranial magnetic stimulation of 25 ms (PAS25) was performed in patients with HFA/AS (n=9; eight males, one female; mean age 17y 11mo, SD 4y 5mo) and in typically developing age-matched volunteers (n=9; five males, four females; mean age 22y 4mo, SD 5y 2mo). The amplitude of motor-evoked potentials was measured before PAS25, immediately after stimulation, and 30 minutes and 60 minutes later. A PAS protocol adapted to individual N20 latency (PASN20+2) was performed in six additional patients with HFA/AS. Short-interval intracortical inhibition was measured using paired-pulse stimulation. Results In contrast to the typically developing participants, the patients with HFA/AS did not show a significant increase in motor-evoked potentials after PAS25. This finding could also be demonstrated after adaptation for N20 latency. Short-interval intracortical inhibition of patients with HFA/AS was normal compared with the comparison group and did not correlate with PAS effect. Interpretation Our results show a significant impairment of LTP-like plasticity induced by PAS in individuals with HFA/AS compared with typically developing participants. This finding is in accordance with results from animal studies as well as human studies. Impaired LTP-like plasticity in patients with HFA/AS points towards reduced excitatory synaptic connectivity and deficits in sensory-motor integration in these patients.

Background Motor learning takes place in several phases. Animal experiments suggest that synaptic plasticity plays an important role in acquisition of motor skills, whereas retention of motor performance is most likely achieved by other mechanisms. Objective/hypothesis This study compared two spacing approaches and investigated the time course of synaptic plasticity after spaced motor practice (MP). Methods Twenty subjects performed a ballistic thumb flexion task in sessions of 6 × 10 minutes or 12 × 5 minutes. We measured peak acceleration of the target movement throughout the experiment and cortical excitability more than 60 minutes after MP via transcranial magnetic stimulation (TMS). After a retention period, both parameters were re-evaluated. Results Mean peak acceleration of the target movement significantly increased (6 × 10 minutes: 21.61 m/s 2 versus 30.80 m/s 2 , P = .002; 12 × 5 minutes: 18.52 m/s 2 versus 29.65 m/s 2 , P = .01). In both training groups, motor evoked potential (MEP) amplitudes of the trained muscle continuously increased after MP (6 × 10 min: 0.93 mV versus 1.57 mV, P = .19; 12 × 5 min: 0.90 mV versus 1.76 mV, P = .004). After the retention period, motor performance was still significantly enhanced, whereas MEP amplitudes were no longer significantly increased. Conclusions These findings do not provide evidence that in small scale motor learning the duration of practice and rest influences behavioral improvement or induction of cortical plasticity. Our study demonstrates that cortical plasticity after MP displays a dynamical time course that might be caused by different mechanisms.

Fast synchronous neurotransmitter release at the presynaptic active zone is triggered by local Ca2+ signals, which are confined in their spatiotemporal extent by endogenous Ca2+ buffers. However, it remains elusive how rapid and reliable Ca2+ signaling can be sustained during repetitive release. Here, we established quantitative two-photon Ca2+ imaging in cerebellar mossy fiber boutons, which fire at exceptionally high rates. We show that endogenous fixed buffers have a surprisingly low Ca2+-binding ratio (similar to 15) and low affinity, whereas mobile buffers have high affinity. Experimentally constrained modeling revealed that the low endogenous buffering promotes fast clearance of Ca2+ from the active zone during repetitive firing. Measuring Ca2+ signals at different distances from active zones with ultra-high-resolution confirmed our model predictions. Our results lead to the concept that reduced Ca2+ buffering enables fast active zone Ca2+ signaling, suggesting that the strength of endogenous Ca2+ buffering limits the rate of synchronous synaptic transmission.

Cerebellar granule cells (GCs), the smallest neurons in the brain, have on average four short dendrites that receive high-frequency mossy fiber inputs conveying sensory information. The short length of the dendrites suggests that GCs are electrotonically compact allowing unfiltered integration of dendritic inputs. The small average diameter of the dendrites (~0.7 µm), however, argues for dendritic filtering. Previous studies based on somatic recordings and modeling indicated that GCs are electrotonically extremely compact. Here, we performed patch-clamp recordings from GC dendrites in acute brain slices of mice to directly analyze the electrotonic properties of GCs. Strikingly, the input resistance did not differ significantly between dendrites and somata of GCs. Furthermore, spontaneous excitatory postsynaptic potentials (EPSP) were similar in amplitude at dendritic and somatic recording sites. From the dendritic and somatic input resistances we determined parameters characterizing the electrotonic compactness of GCs. These data directly demonstrate that cerebellar GCs are electrotonically compact and thus ideally suited for efficient high-frequency information transfer.

A full-sine (biphasic) pulse waveform is most commonly used for repetitive transcranial magnetic stimulation (TMS), but little is known about how variations in duration or amplitude of distinct pulse segments influence the effectiveness of a single TMS pulse to elicit a corticomotor response. Using a novel TMS device, we systematically varied the configuration of full-sine pulses to assess the impact of configuration changes on resting motor threshold (RMT) as measure of stimulation effectiveness with single-pulse TMS of the non-dominant motor hand area (M1). In young healthy volunteers, we (i) compared monophasic, half-sine, and full-sine pulses, (ii) applied two-segment pulses consisting of two identical half-sines, and (iii) manipulated amplitude, duration, and current direction of the first or second full-sine pulse half-segments. RMT was significantly higher using half-sine or monophasic pulses compared with full-sine. Pulses combining two half-sines of identical polarity and duration were also characterized by higher RMT than full-sine stimuli resulting. For full-sine stimuli, decreasing the amplitude of the half-segment inducing posterior-anterior oriented current in M1 resulted in considerably higher RMT, whereas varying the amplitude of the half-segment inducing anterior-posterior current had a smaller effect. These findings provide direct experimental evidence that the pulse segment inducing a posterior-anterior directed current in M1 contributes most to corticospinal pathway excitation. Preferential excitation of neuronal target cells in the posterior-anterior segment or targeting of different neuronal structures by the two half-segments can explain this result. Thus, our findings help understanding the mechanisms of neural stimulation by full-sine TMS.

Aim Early unilateral brain lesions can lead to a persistence of ipsilateral corticospinal projections from the contralesional hemisphere, which can enable the contralesional hemisphere to exert motor control over the paretic hand. In contrast to the primary motor representation (M1), the primary somatosensory representation (S1) of the paretic hand always remains in the lesioned hemisphere. Here, we report on differences in exercise-induced neuroplasticity between individuals with such ipsilateral motor projections (ipsi) and individuals with early unilateral lesions but ‘healthy’ contralateral motor projections (contra). Method Sixteen children and young adults with congenital hemiparesis participated in the study (contralateral [Contra] group: n=7, four females, three males; age range 10–30y, median age 16y; ipsilateral [Ipsi] group: n=9, four females, five males; age range 11–31y, median age 12y; Manual Ability Classification System levels I to II in all individuals in both groups). The participants underwent a 12-day intervention of constraint-induced movement therapy (CIMT), consisting of individual training (2h/d) and group training (8h/d). Before and after CIMT, hand function was tested using the Wolf Motor Function Test (WMFT) and diverging neuroplastic effects were observed by transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG). Statistical analysis of TMS data was performed using the non-parametric Wilcoxon signed-rank test for pair-wise comparison; for fMRI standard statistical parametric and non-parametric mapping (SPM5, SnPM3) procedures (first level/second level) were carried out. Statistical analyses of MEG data involved analyses of variance (ANOVA) and t-tests. Results While MEG demonstrated a significant increase in S1 activation in both groups (p=0.012), TMS showed a decrease in M1 excitability in the Ipsi group (p=0.036), but an increase in M1 excitability in the Contra group (p=0.043). Similarly, fMRI showed a decrease in M1 activation in the Ipsi group, but an increase in activation in the M1–S1 region in the Contra group (for both groups p

Background Transcranial magnetic stimulation (TMS) of the human primary motor hand area (M1-HAND) can produce multiple descending volleys in fast-conducting corticospinal neurons, especially so-called indirect waves (I-waves) resulting from trans-synaptic excitation. Facilitatory interaction between these I-waves can be studied non-invasively using a paired-pulse paradigm referred to as short-interval intracortical facilitation (SICF). Objective/hypothesis We examined whether SICF depends on waveform and current direction of the TMS pulses. Methods In young healthy volunteers, we applied single- and paired-pulse TMS to M1-HAND. We probed SICF by pairs of monophasic or half-sine pulses at suprathreshold stimulation intensity and inter-stimulus intervals (ISIs) between 1.0 and 5.0 ms. For monophasic paired-pulse stimulation, both pulses had either a posterior–anterior (PA) or anterior–posterior (AP) current direction (AP–AP or PA–PA), whereas current direction was reversed between first and second pulse for half-sine paired-pulse stimulation (PA–AP and AP–PA). Results Monophasic AP–AP stimulation resulted in stronger early SICF at 1.4 ms relative to late SICF at 2.8 and 4.4 ms, whereas monophasic PA–PA stimulation produced SICF of comparable size at all three peaks. With half-sine stimulation the third SICF peak was reduced for PA–AP current orientation compared with AP–PA. Conclusion SICF elicited using monophasic as well as half-sine pulses is affected by current direction at clearly suprathreshold intensities. The impact of current orientation is stronger for monophasic compared with half-sine pulses. The direction-specific effect of paired-pulse TMS on the strength of early versus late SICF shows that different cortical circuits mediate early and late SICF.

Fragestellung: Das Noonan-Syndrom (NS; OMIM 163950) wird durch Genmutationen verursacht, welche zu einer Hyperaktivitat des Ras-Signalwegs fuhren. Aktuelle in-vitro Studien konnten einen Zusammenhang zwischen beeintrachtigter Langzeitpotenzierung (LTP) und einer Hyperaktivitat des Ras-Signalwegs zeigen. Zusatzlich ist die Induktion synaptischer Plastizitat durch gepaarte assoziative Stimulastion (PAS) beim Menschen stark aufmerksamkeitsabhangig. Daher war es Ziel unserer Studie, die synaptische Plastizitat bei gesunden Probanden sowie Patienten mit NS unter verschiedenen Aufmerksamkeitsbedingungen zu untersuchen.

Over a century ago, the Spanish anatomist Ramón y Cajal described ‘mossy fibres’ in the hippocampus and the cerebellum, which contain several presynaptic boutons. Technical improvements in recent decades have allowed direct patch-clamp recordings from both hippocampal and cerebellar mossy fibre boutons (hMFBs and cMFBs, respectively), making them ideal models to study fundamental properties of synaptic transmission. hMFBs and cMFBs have similar size and shape, but each hMFB contacts one postsynaptic hippocampal CA3 pyramidal neuron, while each cMFB contacts ∼50 cerebellar granule cells. Furthermore, hMFBs and cMFBs differ in terms of their functional specialization. At hMFBs, a large number of release-ready vesicles and low release probability (

We aimed to investigate the induction of long-term potentiation (LTP)-like plasticity by paired associative stimulation (PAS) in patients with high-functioning autism and Asperger syndrome (HFA/AS).PAS with an interstimulus interval between electrical and transcranial magnetic stimulation of 25 ms (PAS(25)) was performed in patients with HFA/AS (n=9; eight males, one female; mean age 17 y 11 mo, SD 4 y 5 mo) and in typically developing age-matched volunteers (n=9; five males, four females; mean age 22 y 4 mo, SD 5 y 2 mo). The amplitude of motor-evoked potentials was measured before PAS(25), immediately after stimulation, and 30 minutes and 60 minutes later. A PAS protocol adapted to individual N20 latency (PAS(N20+2)) was performed in six additional patients with HFA/AS. Short-interval intracortical inhibition was measured using paired-pulse stimulation.In contrast to the typically developing participants, the patients with HFA/AS did not show a significant increase in motor-evoked potentials after PAS(25). This finding could also be demonstrated after adaptation for N20 latency. Short-interval intracortical inhibition of patients with HFA/AS was normal compared with the comparison group and did not correlate with PAS effect.Our results show a significant impairment of LTP-like plasticity induced by PAS in individuals with HFA/AS compared with typically developing participants. This finding is in accordance with results from animal studies as well as human studies. Impaired LTP-like plasticity in patients with HFA/AS points towards reduced excitatory synaptic connectivity and deficits in sensory-motor integration in these patients.

Objective Noonan syndrome (NS; OMIM 163950 ) is a developmental disorder caused by activating mutations in various components of the RAS-MAPK pathway. Recent in vitro studies demonstrated impairment of synaptic plasticity caused by RAS-MAPK pathway hyperactivity. Induction of synaptic plasticity critically depends on the level of attention. We therefore studied the induction of synaptic plasticity in patients with NS and healthy volunteers under different conditions of attention using transcranial magnetic stimulation. Methods We investigated 10 patients with NS and healthy controls (HC) using paired associative stimulation (PAS) with different attention levels (unspecific, visual and electrical attention control). Changes in motor evoked potential (MEP) amplitudes were assessed immediately after as well as 30 and 60 min after PAS. Results We demonstrated that MEP amplitudes of healthy controls significantly increased from 1.00 ± 0.17 to 1.74 ± 0.50 mV (p = 0.001), which was not seen in patients with Noonan-Syndrome (0.88 ± 0.09 to 1.10 ± 0.48 mV, p = 0.148) and there was a significant difference between both groups (p = 0.003) when using an unspecific attention control. Under specific electrical attention control, MEP amplitudes decreased significantly in patients with NS, whereas a visual attention focus diminished synaptic plasticity in healthy controls. Conclusion Our study provides evidence that synaptic plasticity is impaired in patients with NS, which is probably a consequence of constitutive activity of the RAS-MAPK pathway. The induction of synaptic plasticity in these patients critically depends on attention. Significance This is the first study that indicates reduced synaptic plasticity in patients with a RAS-pathway disorder. Our results may have direct implications for learning and memory strategies in patients with a RAS-pathway disorder.

Background: Transcranial magnetic stimulation (TMS) commonly uses so-called monophasic pulses where the initial rapidly changing current flow is followed by a critically dampened return current. It has been shown that a monophasic TMS pulse preferentially excites different cortical circuits in the human motor hand area (M1-HAND), if the induced tissue current has a posterior-to-anterior (PA) or anterior-to-posterior (AP) direction. Here we tested whether similar direction-specific effects could be elicited in M1-HAND using TMS pulses with a half-sine wave configuration. Results: In 10 young participants, we applied half-sine pulses to the right M1-HAND which elicited PA or AP currents with respect to the orientation of the central sulcus. Measurements of the motor evoked potential (MEP) revealed that PA half-sine stimulation resulted in lower resting motor threshold (RMT) than AP stimulation. When stimulus intensity (SI) was gradually increased as percentage of maximal stimulator output, the stimulus–response curve (SRC) of MEP amplitude showed a leftward shift for PA as opposed to AP half-sine stimulation. Further, MEP latencies were approximately 1 ms shorter for PA relative to AP half-sine stimulation across the entire SI range tested. When adjusting SI to the respective RMT of PA and AP stimulation, the direction-specific differences in MEP latencies persisted, while the gain function of MEP amplitudes was comparable for PA and AP stimulation. Conclusions: Using half-sine pulse configuration, single-pulse TMS elicits consistent direction-specific effects in M1-HAND that are similar to TMS with monophasic pulses. The longer MEP latency for AP half-sine stimulation suggests that PA and AP half-sine stimulation preferentially activates different sets of cortical neurons that are involved in the generation of different corticospinal descending volleys. Keywords: Transcranial magnetic stimulation, Current direction, Half-sine stimulus, I-waves, Stimulus–response curves, Motor cortex * Correspondence: volker.mall@tum.de †Equal contributors 1Department of Pediatrics, Technical University Munich, Kinderzentrum München gemeinnützige GmbH, Heiglhofstrasse 63, Munich 81377, Germany 2Department of Paediatrics and Adolescent Medicine, Division of Neuropaediatrics and Muscular Disorders, University Medical Centre Freiburg, Mathildenstr 1, Freiburg 79106, Germany Full list of author information is available at the end of the article © 2012 peerReviewed

Background Neuronal plasticity is the physiological correlate of learning and memory. In animal experiments, synaptic (i.e. long-term potentiation (LTP) and depression (LTD)) and intrinsic plasticity are distinguished. In human motor cortex, cortical plasticity can be demonstrated using transcranial magnetic stimulation (TMS). Changes in motor-evoked potential (MEP) amplitudes most likely represent synaptic plasticity and are thus termed LTP-like and LTD-like plasticity. Objective/hypothesis We investigated the role of changes of motor threshold and their relation to changes of MEP amplitudes. Methods We induced plasticity by paired associative stimulation (PAS) with 25 ms or 10 ms inter-stimulus interval or by motor practice (MP) in 64 healthy subjects aged 18–31 years (median 24.0). Results We observed changes of MEP amplitudes and motor threshold after PAS[25], PAS[10] and MP. In all three protocols, long-term individual changes in MEP amplitude were inversely correlated to changes in motor threshold (PAS[25]: P = .003, n = 36; PAS[10]: P = .038, n = 19; MP: P = .041, n = 19). Conclusion We conclude that changes of MEP amplitudes and MT represent two indices of motor cortex plasticity. Whereas increases and decreases in MEP amplitude are assumed to represent LTP-like or LTD-like synaptic plasticity of motor cortex output neurons, changes of MT may be considered as a correlate of intrinsic plasticity.

Background Previous studies have shown that the efficacy of transcranial magnetic stimulation (TMS) to excite corticospinal neurons depends on pulse waveform. Objective/Hypotheses In this study, we examined whether the effectiveness of polyphasic TMS can be increased by using a pulse profile that consists of multiple sine cycles. Methods In eight subjects, single-pulse TMS was applied to the left primary motor hand area through a round coil attached to a stimulator device that generated polyphasic pulses consisting of one to six full-sine cycles with a cycle length of 86 μs. In different blocks, we varied the number of sine cycles per pulse and recorded the motor-evoked potential (MEP) from the right first dorsal interosseus muscle. For each stimulus type, we determined resting motor threshold (RMT), stimulus-response curve (SRC), and mean MEP amplitude evoked at maximal stimulator output to assess the efficacy of stimulation. Results Multicycle pulses were more effective than a single full-sine cycle in exciting corticospinal neurons. TMS with multicycle pulses resulted in lower RMT, larger MEP amplitudes at maximal stimulator output and a steeper slope of the SRC relative to a TMS pulse consisting of a single-sine cycle. The increase in efficacy was already evident when two full-sine cycles were used and did not increase further by adding more cycles to the TMS pulse. Conclusions Increasing the number of full-sine cycles per pulse can improve the efficacy of TMS to excite corticospinal neurons, but there is no simple linear relationship between the number of cycles and TMS efficacy.

Objective: Noonan syndrome (NS; OMIM 163950) is a developmental disorder characterized by short stature, congenital heart defects, facial anomalies and variable learning deficits. NS is caused by activating mutations in various components of the RAS-MAPK pathway. Recent in vitro studies demonstrated impairment of synaptic plasticity caused by RAS-MAPK pathway hyperactivity. We therefore intended to find a clue to synaptic plasticity in patients with NS. Methods: We investigated 8 patients with Noonan syndrome and an age and gender matched control group using paired associative stimulation (PAS). Changes in MEP amplitudes were assessed immediately after as well as 30 and 60 minutes after PAS. Results: We demonstrated that MEP amplitudes of healthy controls significantly increased from 1.03±0.18 to 1.81±0.61 mV (p=0.006), which was not seen in patients with Noonan-Syndrome (0.88±0.1 to 1.2±0.49 mV, p=0.103) and that there was a significant difference between both groups 60min after PAS (p=0.044). Conclusions: Our study provides first evidence that synaptic plasticity is impaired in patients with NS which is probably a consequence of constitutive activity of the RAS-MAPK pathway. Significance: This is the first study that indicated impaired synaptic plasticity in patients with a RAS-pathway disorder.

Introduction: It has been shown from invasive epidural recordings that in transcranial magnetic stimulation (TMS) a current in the brain flowing from a posterior to an anterior (p.a.) direction mainly evokes I1, I2 and I3 waves whereas a current flowing from an anterior to a posterior direction mainly evokes I3 waves. This leads to the hypotheses that in p.a. current direction the motor threshold (MT) is lower, motor evoked potentials (MEPs) are higher and latency is shorter than in a.p. direction. The aim of this study was to re-evaluate the inconsistent results in literature by means of a stimulation technique that enabled us to change the current direction without turning the coil. Methods: We investigated n=23 healthy subjects (female: n=12; mean age: 26.2±1.9 years). We recorded the MT, MEP amplitude to target 400µV (SI400µV), MT adapted IO curves and maximum stimulator output (MSO) adapted IO curves in a.p. and p.a. current direction (monophasic waveform) with the P-Stim 160 stimulator (Mag and More, Germany). Results: MT was significantly lower (p=0.003), MEP amplitudes (SI400µV) were significantly higher (p

Background One major attribute of transcranial magnetic stimulation (TMS) is the variability of motor-evoked potential (MEP) amplitudes, to which variations of coil positioning may contribute. Navigated TMS allows the investigator to retrieve a stimulation site with an accuracy of 2.5 mm and to retain coil position with low spatial divergence during stimulation. Objective The purpose of this study was to investigate whether increased spatial constancy of the coil using a navigational system decreases the variability of MEP amplitudes and increases their reproducibility between different points in time of investigation. Methods We investigated eight healthy subjects (mean age 23.8 ± 1.2 years, range 22-25, four women, four men) at three different points in time with and without an optically tracked frameless navigational device, respectively. Input-output curves, motor threshold, and MEP amplitudes were recorded. We calculated the coefficient of variation as statistical parameter of variability. Reproducibility between different sessions was assessed via the MEP amplitude. Results The coefficient of variance of MEP amplitudes did not show a distinct difference between navigated and non-navigated TMS in input-output curves. MEP amplitudes, indicating reproducibility, did not significantly differ between sessions with and without navigated TMS, either. Conclusions Our results do not support the hypothesis that increased spatial constancy using a navigational system improves variability and reproducibility of MEP amplitudes. Variability of MEPs might mainly be due to not influenceable neurophysiologic factors such as undulant cortical excitability and spinal desynchronization.

Objective Low-frequency stimulation, which does not induce long-term potentiation (LTP) or long-term potentiation (LTD) by itself, suppresses consecutive LTP or LTD induction in vitro. We tested whether a similar interaction occurs in the human motor cortex. Methods LTP- or LTD-like plasticity was induced using paired associative stimulation (PAS) with 25 and 10 ms interstimulus interval and conditioned by suprathreshold repetitive transcranial magnetic stimulation (rTMS) at a frequency of 0.1 Hz. Results RTMS completely abolished the significant increase of motor-evoked potential (MEP) amplitudes after PAS25ms (PAS25ms only: 1.05 ± 0.14 to 1.76 ± 0.66 mV, p = 0.001; rTMS + PAS25ms: 1.08 ± 0.18 to 1.02 ± 0.44 mV, n.s.) and also abolished the significant decrease of MEP amplitudes after PAS10ms (PAS10ms only: 1.00 ± 0.14 to 0.73 ± 0.32 mV; rTMS + PAS10ms: 1.15 ± 0.35 to 1.25 ± 0.43 mV, p = 0.006). RTMS alone did not significantly alter MEP amplitudes but increased SICI and LICI. Conclusions Low frequency stimulation increases intracortical inhibition and occludes LTP- and LTD-like plasticity in the human motor cortex. Significance This finding supports the concept that metaplasticity in the human motor cortex follows similar rules as metaplasticity in in vitro experiments.

Hintergrund: Die Wechselwirkungen zwischen neuronale Plastizitat induzierenden Protokollen werden durch die Bienenstock-Cooper-Munroe-(BCM)-Theorie beschrieben, nicht hingegen die im Tierexperiment beschriebene Blockade von Long-Term Potentiation (LTP) und Long-Term Depression (LTD) durch niederfrequente Stimulation. Methoden: Repetitive transkranielle Magnetstimulation (rTMS) mit einer Frequenz von 0,1Hz wurde vor Paired Associative Stimulatioon (PAS) mit den Interstimulusintervallen 25ms und 10ms durchgefuhrt (n=10 fur PAS_25ms, n=8 fur PAS_10ms). Bei den gleichen Probanden wurde zum Vergleich nur PAS angewendet. Ergebnisse: PAS_25ms fuhrte zu einer Vergroserung der Amplituden motorisch evozierter Potentiale (MEP) von 1,10mV zu 1,82mV (p