A Developmental Switch for Hebbian Plasticity

Hebbian forms of synaptic plasticity are required for the orderly development of sensory circuits in the brain and are powerful modulators of learning and memory in adulthood. During development, emergence of Hebbian plasticity leads to formation of functional circuits. By modeling the dynamics of neurotransmitter release during early postnatal cortical development we show that a developmentally regulated switch in vesicle exocytosis mode triggers associative (i.e. Hebbian) plasticity. Early in development spontaneous vesicle exocytosis (SVE), often considered as ''synaptic noise'', is important for homogenization of synaptic weights and maintenance of synaptic weights in the appropriate dynamic range. Our results demonstrate that SVE has a permissive, whereas subsequent evoked vesicle exocytosis (EVE) has an instructive role in the expression of Hebbian plasticity. A timed onset for Hebbian plasticity can be achieved by switching from SVE to EVE and the balance between SVE and EVE can control the effective rate of Hebbian plasticity. We further show that this developmental switch in neurotransmitter release mode enables maturation of spike-timing dependent plasticity. A mis-timed or inadequate SVE to EVE switch may lead to malformation of brain networks thereby contributing to the etiology of neurodevelopmental disorders.     

Indole Can Act as an Extracellular Signal in Escherichia coli

Previous work has shown that lacZ fusions to the cysK, astD, tnaB, and gabT genes in Escherichia coli are activated by self-produced extracellular signals. Using a combination of ethyl acetate extraction, reversed-phase C(18) chromatography, and thin-layer chromatography, we have purified an extracellular activating signal from E. coli supernatants. Mass spectrometry revealed a molecule with an m/z peak of 117, consistent with indole. Nuclear magnetic resonance analysis of the purified E. coli factor and synthetic indole revealed identical profiles. Using synthetic indole, a dose-dependent activation was observed with lacZ fusions to the gabT, astD, and tnaB genes. However, cysK::lacZ and several control fusions were not significantly activated by indole. Conditioned medium prepared from a tnaA (tryptophanase) mutant, deficient in indole production, supported 26 to 41% lower activation of the gabT and astD fusions. The residual level of activation may be due to a second activating signal. Activation of the tnaB::lacZ fusion was reduced by greater than 70% in conditioned medium from a tnaA mutant.     

Nasal Epithelial Cells Can Act as a Physiological Surrogate for Paediatric Asthma Studies

Introduction

Differentiated paediatric epithelial cells can be used to study the role of epithelial cells in asthma. Nasal epithelial cells are easier to obtain and may act as a surrogate for bronchial epithelium in asthma studies. We assessed the suitability of nasal epithelium from asthmatic children to be a surrogate for bronchial epithelium using air-liquid interface cultures.

Methods

Paired nasal and bronchial epithelial cells from asthmatic children (n = 9) were differentiated for 28 days under unstimulated and IL-13-stimulated conditions. Morphological and physiological markers were analysed using immunocytochemistry, transepithelial-electrical-resistance, Quantitative Real-time-PCR, ELISA and multiplex cytokine/chemokine analysis.

Results

Physiologically, nasal epithelial cells from asthmatic children exhibit similar cytokine responses to stimulation with IL-13 compared with paired bronchial epithelial cells. Morphologically however, nasal epithelial cells differed significantly from bronchial epithelial cells from asthmatic patients under unstimulated and IL-13-stimulated conditions. Nasal epithelial cells exhibited lower proliferation/differentiation rates and lower percentages of goblet and ciliated cells when unstimulated, while exhibiting a diminished and varied response to IL-13.

Conclusions

We conclude that morphologically, nasal epithelial cells would not be a suitable surrogate due to a significantly lower rate of proliferation and differentiation of goblet and ciliated cells. Physiologically, nasal epithelial cells respond similarly to exogenous stimulation with IL-13 in cytokine production and could be used as a physiological surrogate in the event that bronchial epithelial cells are not available.     

Nucleolar Integrity Is Required for the Maintenance of Long-Term Synaptic Plasticity

Long-term memory (LTM) formation requires new protein synthesis and new gene expression. Based on our work in Aplysia, we hypothesized that the rRNA genes, stimulation-dependent targets of the enzyme Poly(ADP-ribose) polymerase-1 (PARP-1), are primary effectors of the activity-dependent changes in synaptic function that maintain synaptic plasticity and memory. Using electrophysiology, immunohistochemistry, pharmacology and molecular biology techniques, we show here, for the first time, that the maintenance of forskolin-induced late-phase long-term potentiation (L-LTP) in mouse hippocampal slices requires nucleolar integrity and the expression of new rRNAs. The activity-dependent upregulation of rRNA, as well as L-LTP expression, are poly(ADP-ribosyl)ation (PAR) dependent and accompanied by an increase in nuclear PARP-1 and Poly(ADP) ribose molecules (pADPr) after forskolin stimulation. The upregulation of PARP-1 and pADPr is regulated by Protein kinase A (PKA) and extracellular signal-regulated kinase (ERK)—two kinases strongly associated with long-term plasticity and learning and memory. Selective inhibition of RNA Polymerase I (Pol I), responsible for the synthesis of precursor rRNA, results in the segmentation of nucleoli, the exclusion of PARP-1 from functional nucleolar compartments and disrupted L-LTP maintenance. Taken as a whole, these results suggest that new rRNAs (28S, 18S, and 5.8S ribosomal components)—hence, new ribosomes and nucleoli integrity—are required for the maintenance of long-term synaptic plasticity. This provides a mechanistic link between stimulation-dependent gene expression and the new protein synthesis known to be required for memory consolidation.     

Fgf9 and Wnt4 Act as Antagonistic Signals to Regulate Mammalian Sex Determination

The genes encoding members of the wingless-related MMTV integration site (WNT) and fibroblast growth factor (FGF) families coordinate growth, morphogenesis, and differentiation in many fields of cells during development. In the mouse, Fgf9 and Wnt4 are expressed in gonads of both sexes prior to sex determination. Loss of Fgf9 leads to XY sex reversal, whereas loss of Wnt4 results in partial testis development in XX gonads. However, the relationship between these signals and the male sex-determining gene, Sry, was unknown. We show through gain- and loss-of-function experiments that fibroblast growth factor 9 (FGF9) and WNT4 act as opposing signals to regulate sex determination. In the mouse XY gonad, Sry normally initiates a feed-forward loop between Sox9 and Fgf9, which up-regulates Fgf9 and represses Wnt4 to establish the testis pathway. Surprisingly, loss of Wnt4 in XX gonads is sufficient to up-regulate Fgf9 and Sox9 in the absence of Sry. These data suggest that the fate of the gonad is controlled by antagonism between Fgf9 and Wnt4. The role of the male sex-determining switch— Sry in the case of mammals—is to tip the balance between these underlying patterning signals. In principle, sex determination in other vertebrates may operate through any switch that introduces an imbalance between these two signaling pathways.     

A New Approach for Determining Phase Response Curves Reveals that Purkinje Cells Can Act as Perfect Integrators

Cerebellar Purkinje cells display complex intrinsic dynamics. They fire spontaneously, exhibit bistability, and via mutual network interactions are involved in the generation of high frequency oscillations and travelling waves of activity. To probe the dynamical properties of Purkinje cells we measured their phase response curves (PRCs). PRCs quantify the change in spike phase caused by a stimulus as a function of its temporal position within the interspike interval, and are widely used to predict neuronal responses to more complex stimulus patterns. Significant variability in the interspike interval during spontaneous firing can lead to PRCs with a low signal-to-noise ratio, requiring averaging over thousands of trials. We show using electrophysiological experiments and simulations that the PRC calculated in the traditional way by sampling the interspike interval with brief current pulses is biased. We introduce a corrected approach for calculating PRCs which eliminates this bias. Using our new approach, we show that Purkinje cell PRCs change qualitatively depending on the firing frequency of the cell. At high firing rates, Purkinje cells exhibit single-peaked, or monophasic PRCs. Surprisingly, at low firing rates, Purkinje cell PRCs are largely independent of phase, resembling PRCs of ideal non-leaky integrate-and-fire neurons. These results indicate that Purkinje cells can act as perfect integrators at low firing rates, and that the integration mode of Purkinje cells depends on their firing rate.     

Aha1 Can Act as an Autonomous Chaperone to Prevent Aggregation of Stressed Proteins

Aha1 (activator of Hsp90 ATPase) stimulates the ATPase activity of the molecular chaperone Hsp90 to accelerate the conformational cycle during which client proteins attain their final shape. Thereby, Aha1 promotes effective folding of Hsp90-dependent clients such as steroid receptors and many kinases involved in cellular signaling. In our current study, we find that Aha1 plays a novel, additional role beyond regulating the Hsp90 ATP hydrolysis rate. We propose a new concept suggesting that Aha1 acts as an autonomous chaperone and associates with stress-denatured proteins to prevent them from aggregation similar to the chaperonin GroEL. Our study reveals that an N-terminal sequence of 22 amino acids, present in human but absent from yeast Aha1, is critical for this capability. However, in lieu of fostering their refolding, Aha1 allows ubiquitination of bound clients by the E3 ubiquitin ligase CHIP. Accordingly, Aha1 may promote disposal of folding defective proteins by the cellular protein quality control.     

Honey Bee Inhibitory Signaling Is Tuned to Threat Severity and Can Act as a Colony Alarm Signal

Alarm communication is a key adaptation that helps social groups resist predation and rally defenses. In Asia, the world’s largest hornet, Vespa mandarinia, and the smaller hornet, Vespa velutina, prey upon foragers and nests of the Asian honey bee, Apis cerana. We attacked foragers and colony nest entrances with these predators and provide the first evidence, in social insects, of an alarm signal that encodes graded danger and attack context. We show that, like Apis mellifera, A. cerana possesses a vibrational “stop signal,” which can be triggered by predator attacks upon foragers and inhibits waggle dancing. Large hornet attacks were more dangerous and resulted in higher bee mortality. Per attack at the colony level, large hornets elicited more stop signals than small hornets. Unexpectedly, stop signals elicited by large hornets (SS _{large hornet}) had a significantly higher vibrational fundamental frequency than those elicited by small hornets (SS _{small hornet}) and were more effective at inhibiting waggle dancing. Stop signals resulting from attacks upon the nest entrance (SS _nest) were produced by foragers and guards and were significantly longer in pulse duration than stop signals elicited by attacks upon foragers (SS _forager). Unlike SS _forager, SS _nest were targeted at dancing and non-dancing foragers and had the common effect, tuned to hornet threat level, of inhibiting bee departures from the safe interior of the nest. Meanwhile, nest defenders were triggered by the bee alarm pheromone and live hornet presence to heat-ball the hornet. In A. cerana, sophisticated recruitment communication that encodes food location, the waggle dance, is therefore matched with an inhibitory/alarm signal that encodes information about the context of danger and its threat level.     

Huntingtin Is Critical Both Pre- and Postsynaptically for Long-Term Learning-Related Synaptic Plasticity in Aplysia

Patients with Huntington’s disease exhibit memory and cognitive deficits many years before manifesting motor disturbances. Similarly, several studies have shown that deficits in long-term synaptic plasticity, a cellular basis of memory formation and storage, occur well before motor disturbances in the hippocampus of the transgenic mouse models of Huntington’s disease. The autosomal dominant inheritance pattern of Huntington’s disease suggests the importance of the mutant protein, huntingtin, in pathogenesis of Huntington’s disease, but wild type huntingtin also has been shown to be important for neuronal functions such as axonal transport. Yet, the role of wild type huntingtin in long-term synaptic plasticity has not been investigated in detail. We identified a huntingtin homolog in the marine snail Aplysia, and find that similar to the expression pattern in mammalian brain, huntingtin is widely expressed in neurons and glial cells. Importantly the expression of mRNAs of huntingtin is upregulated by repeated applications of serotonin, a modulatory transmitter released during learning in Aplysia. Furthermore, we find that huntingtin expression levels are critical, not only in presynaptic sensory neurons, but also in the postsynaptic motor neurons for serotonin-induced long-term facilitation at the sensory-to-motor neuron synapse of the Aplysia gill-withdrawal reflex. These results suggest a key role for huntingtin in long-term memory storage.     

Discharge in a Subthreshold Microwave Beam as an Effective Means for Mercaptan Decomposition

Plasma Physics Reports - A subthreshold microwave discharge in atmospheric-pressure air is used to process mixtures of mercaptans (thiols) with air and with air and methane. It is found that, at...     

Sequence Motifs in Transit Peptides Act as Independent Functional Units and Can Be Transferred to New Sequence Contexts

A large number of nuclear-encoded proteins are imported into chloroplasts after they are translated in the cytosol. Import is mediated by transit peptides (TPs) at the N termini of these proteins. TPs contain many small motifs, each of which is critical for a specific step in the process of chloroplast protein import; however, it remains unknown how these motifs are organized to give rise to TPs with diverse sequences. In this study, we generated various hybrid TPs by swapping domains between Rubisco small subunit (RbcS) and chlorophyll a/b-binding protein, which have highly divergent sequences, and examined the abilities of the resultant TPs to deliver proteins into chloroplasts. Subsequently, we compared the functionality of sequence motifs in the hybrid TPs with those of wild-type TPs. The sequence motifs in the hybrid TPs exhibited three different modes of functionality, depending on their domain composition, as follows: active in both wild-type and hybrid TPs, active in wild-type TPs but inactive in hybrid TPs, and inactive in wild-type TPs but active in hybrid TPs. Moreover, synthetic TPs, in which only three critical motifs from RbcS or chlorophyll a/b-binding protein TPs were incorporated into an unrelated sequence, were able to deliver clients to chloroplasts with a comparable efficiency to RbcS TP. Based on these results, we propose that diverse sequence motifs in TPs are independent functional units that interact with specific translocon components at various steps during protein import and can be transferred to new sequence contexts.The chloroplasts of plant cells have more than 3,000 different types of proteins involved in their functions (Leister, 2003; Li and Chiu, 2010), and more than 90% of these proteins are encoded in the nucleus and translated by cytosolic ribosomes (Li and Chiu, 2010; Lee et al., 2013a). Consequently, one of the most critical processes in chloroplast proteome biogenesis is the specific, posttranslational delivery of these nuclear-encoded proteins to chloroplasts (Jarvis, 2008; Li and Chiu, 2010; Lee et al., 2013a, 2014). Delivery to chloroplasts requires a specific targeting signal whose form depends on the type of protein and its location in the chloroplast. Most proteins imported into the chloroplast contain an N-terminal transit peptide (TP) as a targeting signal (Lee et al., 2006, 2008, 2013a; Chotewutmontri et al., 2012; Li and Teng, 2013). The TP is cleaved off after import into the chloroplast; thus, the proteins that still contain the TP are called preproteins. Despite progress made in previous studies (Lee et al., 2008; Chotewutmontri et al., 2012; Li and Teng, 2013), the types of information encoded by the long TPs, as well as how this information determines translocation through the import channel, remain to be elucidated.One long-lasting question regarding the mechanism of TP-mediated protein import is how TPs can specifically deliver proteins into chloroplasts. In striking contrast to endoplasmic reticulum (ER)-targeting signals, TPs are highly diverse at the primary sequence level and do not converge toward a consensus sequence. The leader sequence, which contains the N-terminal ER-targeting signal, is composed of a stretch of hydrophobic amino acids ranging from 15 to 20 residues. Although the exact sequence is highly variable, the residues tend to be hydrophobic, making a high degree of hydrophobicity a common characteristic feature for both luminal and membrane proteins. Despite their diversity in primary sequence, TPs also share certain characteristics that serve as the basis for the software prediction of chloroplast proteins; these features include an amino acid composition with a high concentration of hydroxylated residues and a lack of acidic residues (Bruce, 2000; Bhushan et al., 2006), an unfolded and extended structure, an α-helix-containing secondary structure that may be induced by binding to the lipids of chloroplasts (Wienk et al., 1999; Bruce, 2000), and an abundance of Pro residues that may contribute to the unstructured nature of TPs (Pilon et al., 1995; Bruce, 2000; Zybailov et al., 2008).These features provide insight into the sequence information carried by TPs. However, we are still far from fully understanding how TPs function in the mechanism of protein import into chloroplasts. Recent studies have identified sequence motifs by analyzing various deletion and substitution mutants (Pilon et al., 1995; Lee et al., 2006, 2008, 2013a; Chotewutmontri et al., 2012). These motifs, or domains, are thought to be involved in the interaction with components of the translocon (Chotewutmontri et al., 2012; Li and Teng, 2013). Moreover, multiple sequence motifs function individually, or in a combinatorial manner, during specific steps of the import process (Lee et al., 2006, 2008, 2009a). In addition, certain motifs share functional redundancy, or are additive or synergistic. However, despite the progress in identifying sequence motifs from different TPs, it remains unknown how the large number of diverse TPs, as a whole, can deliver proteins to chloroplasts. In ER targeting, the targeting machinery recognizes hydrophobicity, a common feature of the leader sequences, but not the primary sequence (Hessa et al., 2005). Therefore, leader sequences with different primary sequences can be recognized by the same molecular machinery. However, in contrast to the leader sequences, the TPs of chloroplast preproteins contain different sets of sequence motifs (Lee et al., 2006, 2008). These observations raise several questions, including (1) how the large number of TPs with different sets of sequence motifs can be recognized by only a few import receptors (Li and Chiu, 2010; Lee et al., 2013a; Li and Teng, 2013), and (2) how TPs can have such diverse sequences while still retaining their function.In this study, we investigated the design principles of TPs with diverse primary sequences. Using TPs of the Rubisco small subunit (RbcS) and chlorophyll a/b-binding protein (Cab) proteins, which have completely different primary sequences and functional motifs (Lee et al., 2006, 2008), we generated hybrid TPs and examined their activities in chloroplast protein import within protoplasts. We provide evidence that sequence motifs are independent functional units that interact with various components of the translocon during import into chloroplasts and can be transferred to new sequence contexts. However, the functionalities as well as the activities of these motifs are greatly dependent on the overall sequence context of, and their positions in, TPs. In addition, we demonstrated that functional synthetic transit peptides (SynTPs) can be generated by incorporating only a few sequence motifs from RbcS and Cab TPs into an unrelated sequence.     

Striatal Astrocytes Act as a Reservoir for L-DOPA

L-DOPA is therapeutically efficacious in patients with Parkinson’s disease (PD), although dopamine (DA) neurons are severely degenerated. Since cortical astrocytes express neutral amino acid transporter (LAT) and DA transporter (DAT), the uptake and metabolism of L-DOPA and DA in striatal astrocytes may influence their availability in the dopaminergic system of PD. To assess possible L-DOPA- and DA-uptake and metabolic properties of striatal astrocytes, we examined the expression of L-DOPA, DA and DAT in striatal astrocytes of hemi-parkinsonian model rats after repeated L-DOPA administration, and measured the contents of L-DOPA, DA and their metabolite in primary cultured striatal astrocytes after L-DOPA/DA treatment. Repeated injections of L-DOPA induced apparent L-DOPA- and DA-immunoreactivities and marked expression of DAT in reactive astrocytes on the lesioned side of the striatum in hemi-parkinsonian rats. Exposure to DA for 4h significantly increased the levels of DA and its metabolite DOPAC in cultured striatal astrocytes. L-DOPA was also markedly increased in cultured striatal astrocytes after 4-h L-DOPA exposure, but DA was not detected 4 or 8h after L-DOPA treatment, despite the expression of aromatic amino acid decarboxylase in astrocytes. Furthermore, the intracellular level of L-DOPA in cultured striatal astrocytes decreased rapidly after removal of extracellular L-DOPA. The results suggest that DA uptaken into striatal astrocytes is rapidly metabolized and that striatal astrocytes act as a reservoir of L-DOPA that govern the uptake or release of L-DOPA depending on extracellular L-DOPA concentration, but are less capable of converting L-DOPA to DA.     

Mushrooms as Rainmakers: How Spores Act as Nuclei for Raindrops

Millions of tons of fungal spores are dispersed in the atmosphere every year. These living cells, along with plant spores and pollen grains, may act as nuclei for condensation of water in clouds. Basidiospores released by mushrooms form a significant proportion of these aerosols, particularly above tropical forests. Mushroom spores are discharged from gills by the rapid displacement of a droplet of fluid on the cell surface. This droplet is formed by the condensation of water on the spore surface stimulated by the secretion of mannitol and other hygroscopic sugars. This fluid is carried with the spore during discharge, but evaporates once the spore is airborne. Using environmental electron microscopy, we have demonstrated that droplets reform on spores in humid air. The kinetics of this process suggest that basidiospores are especially effective as nuclei for the formation of large water drops in clouds. Through this mechanism, mushroom spores may promote rainfall in ecosystems that support large populations of ectomycorrhizal and saprotrophic basidiomycetes. Our research heightens interest in the global significance of the fungi and raises additional concerns about the sustainability of forests that depend on heavy precipitation.     

Responses of Hollow, Septate Stems to Vibrations: Biomechanical Evidence that Nodes Can Act Mechanically as Spring-like Joints

The hypothesis is proposed that nodes of hollow plant stemsact as spring-like joints by storing strain energy when stemsare bent and releasing this energy to elastically restore theoriginal postures of stems when bending forces are removed.This hypothesis was tested by subjecting stem segments consistingof four nodes and three intervening hollow internodes to axialcompressive loads and by determining the natural frequenciesof vibration of their nodes. Compression tests were used todetermine the critical load required to produce elasticallyrecoverable deformations for each of a total of 115 stem segmentsof the grassArundinaria técta(Walt.) Muhl. Each segmentwas observed to flex at or very near its nodes while internodesappeared to act as rigid bars. The natural (fundamental) frequenciesof vibrations of the nodes of these stem segments were subsequentlydetermined and equalled those predicted by engineering theoryassuming that nodes behave as spring-like joints. The data fromresonance frequency tests were then used to calculate the springconstants of stem segments (i.e. the force required to producea unit deflection in stems). These constants were found to agreewith those predicted by theory provided that nodes acted mechanicallyas spring-like joints. The transverse septa of the nodes of20 randomly selected stem segments were perforated with a needleand the spring constants of the impaired nodes were remeasuredand compared with those of the same stems before surgical manipulation.On average, nodal spring constants were reduced by 35%. Thisreduction agreed with the prediction that the perforation ofsepta would significantly reduce the ability of nodes to storestrain energy. Collectively, these results are interpreted tosupport the hypothesis that septate nodes can store and releasestrain energy. The hypothesis is discussed further in lightof the behaviour of a physical model which shows that nodal‘diaphragms’ can substantially stiffen a hollowcylindrical structure, although they are neither essential forthe storage of strain energy nor the subsequent elastic restorationof the model's shape once bending loads are removed. Plant stems; nodes; internodes; strain energy; elastic buckling; Brazier buckling; biomechanics     

Fgf9 and Wnt4 Act as Antagonistic Signals to Regulate Mammalian Sex Determination

The genes encoding members of the wingless-related MMTV integration site (WNT) and fibroblast growth factor (FGF) families coordinate growth, morphogenesis, and differentiation in many fields of cells during development. In the mouse, Fgf9 and Wnt4 are expressed in gonads of both sexes prior to sex determination. Loss of Fgf9 leads to XY sex reversal, whereas loss of Wnt4 results in partial testis development in XX gonads. However, the relationship between these signals and the male sex-determining gene, Sry, was unknown. We show through gain- and loss-of-function experiments that fibroblast growth factor 9 (FGF9) and WNT4 act as opposing signals to regulate sex determination. In the mouse XY gonad, Sry normally initiates a feed-forward loop between Sox9 and Fgf9, which up-regulates Fgf9 and represses Wnt4 to establish the testis pathway. Surprisingly, loss of Wnt4 in XX gonads is sufficient to up-regulate Fgf9 and Sox9 in the absence of Sry. These data suggest that the fate of the gonad is controlled by antagonism between Fgf9 and Wnt4. The role of the male sex-determining switch— Sry in the case of mammals—is to tip the balance between these underlying patterning signals. In principle, sex determination in other vertebrates may operate through any switch that introduces an imbalance between these two signaling pathways.     

Inhibition as a Binary Switch for Excitatory Plasticity in Pyramidal Neurons

Synaptic plasticity is thought to induce memory traces in the brain that are the foundation of learning. To ensure the stability of these traces in the presence of further learning, however, a regulation of plasticity appears beneficial. Here, we take up the recent suggestion that dendritic inhibition can switch plasticity of excitatory synapses on and off by gating backpropagating action potentials (bAPs) and calcium spikes, i.e., by gating the coincidence signals required for Hebbian forms of plasticity. We analyze temporal and spatial constraints of such a gating and investigate whether it is possible to suppress bAPs without a simultaneous annihilation of the forward-directed information flow via excitatory postsynaptic potentials (EPSPs). In a computational analysis of conductance-based multi-compartmental models, we demonstrate that a robust control of bAPs and calcium spikes is possible in an all-or-none manner, enabling a binary switch of coincidence signals and plasticity. The position of inhibitory synapses on the dendritic tree determines the spatial extent of the effect and allows a pathway-specific regulation of plasticity. With appropriate timing, EPSPs can still trigger somatic action potentials, although backpropagating signals are abolished. An annihilation of bAPs requires precisely timed inhibition, while the timing constraints are less stringent for distal calcium spikes. We further show that a wide-spread motif of local circuits—feedforward inhibition—is well suited to provide the temporal precision needed for the control of bAPs. Altogether, our model provides experimentally testable predictions and demonstrates that the inhibitory switch of plasticity can be a robust and attractive mechanism, hence assigning an additional function to the inhibitory elements of neuronal microcircuits beyond modulation of excitability.