Quantal glutamate release is essential for reliable neuronal encodings in cerebral networks

Background

The neurons and synapses work coordinately to program the brain codes of controlling cognition and behaviors. Spike patterns at the presynaptic neurons regulate synaptic transmission. The quantitative regulations of synapse dynamics in spike encoding at the postsynaptic neurons remain unclear.

Methodology/Principal Findings

With dual whole-cell recordings at synapse-paired cells in mouse cortical slices, we have investigated the regulation of synapse dynamics to neuronal spike encoding at cerebral circuits assembled by pyramidal neurons and GABAergic ones. Our studies at unitary synapses show that postsynaptic responses are constant over time, such as glutamate receptor-channel currents at GABAergic neurons and glutamate transport currents at astrocytes, indicating quantal glutamate release. In terms of its physiological impact, our results demonstrate that the signals integrated from quantal glutamatergic synapses drive spike encoding at GABAergic neurons reliably, which in turn precisely set spike encoding at pyramidal neurons through feedback inhibition.

Conclusion/Significance

Our studies provide the evidences for the quantal glutamate release to drive the spike encodings precisely in cortical circuits, which may be essential for programming the reliable codes in the brain to manage well-organized behaviors.     

Axonal transmission in the retina introduces a small dispersion of relative timing in the ganglion cell population response

Background

Visual stimuli elicit action potentials in tens of different retinal ganglion cells. Each ganglion cell type responds with a different latency to a given stimulus, thus transforming the high-dimensional input into a temporal neural code. The timing of the first spikes between different retinal projection neurons cells may further change along axonal transmission. The purpose of this study is to investigate if intraretinal conduction velocity leads to a synchronization or dispersion of the population signal leaving the eye.

Methodology/Principal Findings

We ‘imaged’ the initiation and transmission of light-evoked action potentials along individual axons in the rabbit retina at micron-scale resolution using a high-density multi-transistor array. We measured unimodal conduction velocity distributions (1.3±0.3 m/sec, mean ± SD) for axonal populations at all retinal eccentricities with the exception of the central part that contains myelinated axons. The velocity variance within each piece of retina is caused by ganglion cell types that show narrower and slightly different average velocity tuning. Ganglion cells of the same type respond with similar latency to spatially homogenous stimuli and conduct with similar velocity. For ganglion cells of different type intraretinal conduction velocity and response latency to flashed stimuli are negatively correlated, indicating that differences in first spike timing increase (up to 10 msec). Similarly, the analysis of pair-wise correlated activity in response to white-noise stimuli reveals that conduction velocity and response latency are negatively correlated.

Conclusion/Significance

Intraretinal conduction does not change the relative spike timing between ganglion cells of the same type but increases spike timing differences among ganglion cells of different type. The fastest retinal ganglion cells therefore act as indicators of new stimuli for postsynaptic neurons. The intraretinal dispersion of the population activity will not be compensated by variability in extraretinal conduction times, estimated from data in the literature.     

Long-term activity-dependent plasticity of action potential propagation delay and amplitude in cortical networks

Background

The precise temporal control of neuronal action potentials is essential for regulating many brain functions. From the viewpoint of a neuron, the specific timings of afferent input from the action potentials of its synaptic partners determines whether or not and when that neuron will fire its own action potential. Tuning such input would provide a powerful mechanism to adjust neuron function and in turn, that of the brain. However, axonal plasticity of action potential timing is counter to conventional notions of stable propagation and to the dominant theories of activity-dependent plasticity focusing on synaptic efficacies.

Methodology/Principal Findings

Here we show the occurrence of activity-dependent plasticity of action potential propagation delays (up to 4 ms or 40% after minutes and 13 ms or 74% after hours) and amplitudes (up to 87%). We used a multi-electrode array to induce, detect, and track changes in propagation in multiple neurons while they adapted to different patterned stimuli in controlled neocortical networks in vitro. The changes did not occur when the same stimulation was repeated while blocking ionotropic gabaergic and glutamatergic receptors. Even though induction of changes in action potential timing and amplitude depended on synaptic transmission, the expression of these changes persisted in the presence of the synaptic receptor blockers.

Conclusions/Significance

We conclude that, along with changes in synaptic efficacy, propagation plasticity provides a cellular mechanism to tune neuronal network function in vitro and potentially learning and memory in the brain.     

Impact of Morphometry,Myelinization and Synaptic Current Strength on Spike Conduction in Human and Cat Spiral Ganglion Neurons

Background

Our knowledge about the neural code in the auditory nerve is based to a large extent on experiments on cats. Several anatomical differences between auditory neurons in human and cat are expected to lead to functional differences in speed and safety of spike conduction.

Methodology/Principal Findings

Confocal microscopy was used to systematically evaluate peripheral and central process diameters, commonness of myelination and morphology of spiral ganglion neurons (SGNs) along the cochlea of three human and three cats. Based on these morphometric data, model analysis reveales that spike conduction in SGNs is characterized by four phases: a postsynaptic delay, constant velocity in the peripheral process, a presomatic delay and constant velocity in the central process. The majority of SGNs are type I, connecting the inner hair cells with the brainstem. In contrast to those of humans, type I neurons of the cat are entirely myelinated. Biophysical model evaluation showed delayed and weak spikes in the human soma region as a consequence of a lack of myelin. The simulated spike conduction times are in accordance with normal interwave latencies from auditory brainstem response recordings from man and cat. Simulated 400 pA postsynaptic currents from inner hair cell ribbon synapses were 15 times above threshold. They enforced quick and synchronous spiking. Both of these properties were not present in type II cells as they receive fewer and much weaker (^∼26 pA) synaptic stimuli.

Conclusions/Significance

Wasting synaptic energy boosts spike initiation, which guarantees the rapid transmission of temporal fine structure of auditory signals. However, a lack of myelin in the soma regions of human type I neurons causes a large delay in spike conduction in comparison with cat neurons. The absent myelin, in combination with a longer peripheral process, causes quantitative differences of temporal parameters in the electrically stimulated human cochlea compared to the cat cochlea.     

Experience-Driven Axon Retraction in the Pharmacologically Inactivated Visual Cortex Does Not Require Synaptic Transmission

Background

Experience during early postnatal development plays an important role in the refinement of specific neural connections in the brain. In the mammalian visual system, altered visual experiences induce plastic adaptation of visual cortical responses and guide rearrangements of afferent axons from the lateral geniculate nucleus. Previous studies using visual deprivation demonstrated that the afferents serving an open eye significantly retract when cortical neurons are pharmacologically inhibited by applying a γ-aminobutyric acid type A receptor agonist, muscimol, whereas those serving a deprived eye are rescued from retraction, suggesting that presynaptic activity can lead to the retraction of geniculocortical axons in the absence of postsynaptic activity. Because muscimol application suppresses the spike activity of cortical neurons leaving transmitter release intact at geniculocortical synapses, local synaptic interaction may underlie the retraction of active axons in the inhibited cortex.

Method and Findings

New studies reported here determined whether experience-driven axon retraction can occur in the visual cortex inactivated by blocking synaptic inputs. We inactivated the primary visual cortex of kittens by suppressing synaptic transmission with cortical injections of botulinum neurotoxin type E, which cleaves a synaptic protein, SNAP-25, and blocks transmitter release, and examined the geniculocortical axon morphology in the animals with normal vision and those deprived of vision binocularly. We found that afferent axons in the animals with normal vision showed a significant retraction in the inactivated cortex, as similarly observed in the muscimol-treated cortex, whereas the axons in the binocularly deprived animals were preserved.

Conclusions

Therefore, the experience-driven axon retraction in the inactivated cortex can proceed in the absence of synaptic transmission. These results suggest that presynaptic mechanisms play an important role in the experience-driven refinement of geniculocortical axons.     

Visualizing the Distribution of Synapses from Individual Neurons in the Mouse Brain

Background

Proper function of the mammalian brain relies on the establishment of highly specific synaptic connections among billions of neurons. To understand how complex neural circuits function, it is crucial to precisely describe neuronal connectivity and the distributions of synapses to and from individual neurons.

Methods and Findings

In this study, we present a new genetic synaptic labeling method that relies on expression of a presynaptic marker, synaptophysin-GFP (Syp-GFP) in individual neurons in vivo. We assess the reliability of this method and use it to analyze the spatial patterning of synapses in developing and mature cerebellar granule cells (GCs). In immature GCs, Syp-GFP is distributed in both axonal and dendritic regions. Upon maturation, it becomes strongly enriched in axons. In mature GCs, we analyzed synapses along their ascending segments and parallel fibers. We observe no differences in presynaptic distribution between GCs born at different developmental time points and thus having varied depths of projections in the molecular layer. We found that the mean densities of synapses along the parallel fiber and the ascending segment above the Purkinje cell (PC) layer are statistically indistinguishable, and higher than previous estimates. Interestingly, presynaptic terminals were also found in the ascending segments of GCs below and within the PC layer, with the mean densities two-fold lower than that above the PC layer. The difference in the density of synapses in these parts of the ascending segment likely reflects the regional differences in postsynaptic target cells of GCs.

Conclusions

The ability to visualize synapses of single neurons in vivo is valuable for studying synaptogenesis and synaptic plasticity within individual neurons as well as information flow in neural circuits.     

Glutamatergic neurons induce expression of functional glutamatergic synapses in primary myotubes

Background

The functioning of the nervous system depends upon the specificity of its synaptic contacts. The mechanisms triggering the expression of the appropriate receptors on postsynaptic membrane and the role of the presynaptic partner in the differentiation of postsynaptic structures are little known.

Methods and Findings

To address these questions we cocultured murine primary muscle cells with several glutamatergic neurons, either cortical, cerebellar or hippocampal. Immunofluorescence and electrophysiology analyses revealed that functional excitatory synaptic contacts were formed between glutamatergic neurons and muscle cells. Moreover, immunoprecipitation and immunofluorescence experiments showed that typical anchoring proteins of central excitatory synapses coimmunoprecipitate and colocalize with rapsyn, the acetylcholine receptor anchoring protein at the neuromuscular junction.

Conclusions

These results support an important role of the presynaptic partner in the induction and differentiation of the postsynaptic structures.     

Morphological and physiological evidence of a synaptic connection between the lateral parabrachial nucleus and neurons in the A7 catecholamine cell group in rats

Background

The descending noradrenergic (NAergic) system is one of the important endogenous analgesia systems. It has been suggested that noxious stimuli could activate descending NAergic system; nevertheless, the underlying neuronal circuit remains unclear. As NAergic neurons in the A7 catecholamine cell group (A7) are a part of the descending NAergic system and the lateral parabrachial nucleus (LPB) is an important brainstem structure that relays ascending nociceptive signal, we aimed to test whether LPB neurons have direct synaptic contact with NAergic A7 neurons.

Results

Stereotaxic injections of an anterograde tracer, biotinylated dextran-amine (BDA), were administered to LPB in rats. The BDA-labeled axonal terminals that have physical contacts with tyrosine hydroxylase-positive (presumed noadrenergic) neurons were identified in A7. Consistent with these morphological observations, the excitatory synaptic currents (EPSCs) were readily evoked in NAergic A7 neurons by extracellular stimulation of LPB. The EPSCs evoked by LPB stimulation were blocked by CNQX, a non-NMDA receptor blocker, and AP5, a selective NMDA receptor blocker, showing that LPB-A7 synaptic transmission is glutamatergic. Moreover, the amplitude of LPB-A7 EPSCs was significantly attenuated by DAMGO, a selective μ-opioid receptor agonist, which was associated with an increase in paired-pulse ratio.

Conclusions

Taken together, the above results showed direct synaptic connections between LPB and A7 catecholamine cell group, the function of which is subject to presynaptic modulation by μ-opioid receptors.     

Topological characterization of neuronal arbor morphology via sequence representation: II - global alignment

Background

The increasing abundance of neuromorphological data provides both the opportunity and the challenge to compare massive numbers of neurons from a wide diversity of sources efficiently and effectively. We implemented a modified global alignment algorithm representing axonal and dendritic bifurcations as strings of characters. Sequence alignment quantifies neuronal similarity by identifying branch-level correspondences between trees.

Results

The space generated from pairwise similarities is capable of classifying neuronal arbor types as well as, or better than, traditional topological metrics. Unsupervised cluster analysis produces groups that significantly correspond with known cell classes for axons, dendrites, and pyramidal apical dendrites. Furthermore, the distinguishing consensus topology generated by multiple sequence alignment of a group of neurons reveals their shared branching blueprint. Interestingly, the axons of dendritic-targeting interneurons in the rodent cortex associates with pyramidal axons but apart from the (more topologically symmetric) axons of perisomatic-targeting interneurons.

Conclusions

Global pairwise and multiple sequence alignment of neurite topologies enables detailed comparison of neurites and identification of conserved topological features in alignment-defined clusters. The methods presented also provide a framework for incorporation of additional branch-level morphological features. Moreover, comparison of multiple alignment with motif analysis shows that the two techniques provide complementary information respectively revealing global and local features.

Electronic supplementary material

The online version of this article (doi:10.1186/s12859-015-0605-1) contains supplementary material, which is available to authorized users.     

Reciprocal Regulation of Axonal Filopodia and Outgrowth during Neuromuscular Junction Development

Background

The assembly of the vertebrate neuromuscular junction (NMJ) is initiated when nerve and muscle first contact each other by filopodial processes which are thought to enable close interactions between the synaptic partners and facilitate synaptogenesis. We recently reported that embryonic Xenopus spinal neurons preferentially extended filopodia towards cocultured muscle cells and that basic fibroblast growth factor (bFGF) produced by muscle activated neuronal FGF receptor 1 (FGFR1) to induce filopodia and favor synaptogenesis. Intriguingly, in an earlier study we found that neurotrophins (NTs), a different set of target-derived factors that act through Trk receptor tyrosine kinases, promoted neuronal growth but hindered presynaptic differentiation and NMJ formation. Thus, here we investigated how bFGF- and NT-signals in neurons jointly elicit presynaptic changes during the earliest stages of NMJ development.

Methodology/Principal Findings

Whereas forced expression of wild-type TrkB in neurons reduced filopodial extension and triggered axonal outgrowth, expression of a mutant TrkB lacking the intracellular kinase domain enhanced filopodial growth and slowed axonal advance. Neurons overexpressing wild-type FGFR1 also displayed more filopodia than control neurons, in accord with our previous findings, and, notably, this elevation in filopodial density was suppressed when neurons were chronically treated from the beginning of the culture period with BDNF, the NT that specifically activates TrkB. Conversely, inhibition by BDNF of NMJ formation in nerve-muscle cocultures was partly reversed by the overexpression of bFGF in muscle.

Conclusions

Our results suggest that the balance between neuronal FGFR1- and TrkB-dependent filopodial assembly and axonal outgrowth regulates the establishment of incipient NMJs.     

Heterogeneous nuclear ribonucleoprotein k interacts with Abi-1 at postsynaptic sites and modulates dendritic spine morphology

Background

Abelson-interacting protein 1 (Abi-1) plays an important role for dendritic branching and synapse formation in the central nervous system. It is localized at the postsynaptic density (PSD) and rapidly translocates to the nucleus upon synaptic stimulation. At PSDs Abi-1 is in a complex with several other proteins including WASP/WAVE or cortactin thereby regulating the actin cytoskeleton via the Arp 2/3 complex.

Principal Findings

We identified heterogeneous nuclear ribonucleoprotein K (hnRNPK), a 65 kDa ssDNA/RNA-binding-protein that is involved in multiple intracellular signaling cascades, as a binding partner of Abi-1 at postsynaptic sites. The interaction with the Abi-1 SH3 domain is mediated by the hnRNPK-interaction (KI) domain. We further show that during brain development, hnRNPK expression becomes more and more restricted to granule cells of the cerebellum and hippocampal neurons where it localizes in the cell nucleus as well as in the spine/dendritic compartment. The downregulation of hnRNPK in cultured hippocampal neurons by RNAi results in an enlarged dendritic tree and a significant increase in filopodia formation. This is accompanied by a decrease in the number of mature synapses. Both effects therefore mimic the neuronal morphology after downregulation of Abi-1 mRNA in neurons.

Conclusions

Our findings demonstrate a novel interplay between hnRNPK and Abi-1 in the nucleus and at synaptic sites and show obvious similarities regarding both protein knockdown phenotypes. This indicates that hnRNPK and Abi-1 act synergistic in a multiprotein complex that regulates the crucial balance between filopodia formation and synaptic maturation in neurons.     

Transmission Efficacy and Plasticity in Glutamatergic Synapses Formed by Excitatory Interneurons of the Substantia Gelatinosa in the Rat Spinal Cord

Background

Substantia gelatinosa (SG, lamina II) is a spinal cord region where most unmyelinated primary afferents terminate and the central nociceptive processing begins. The glutamatergic excitatory interneurons (EINs) form the majority of the SG neuron population, but little is known about the mechanisms of signal processing in their synapses.

Methodology

To describe the functional organization and properties of excitatory synapses formed by SG EINs, we did non-invasive recordings from 183 pairs of monosynaptically connected neurons. An intact presynaptic SG EIN was specifically stimulated through the cell-attached pipette while the evoked EPSCs/EPSPs were recorded through perforated-patch from a postsynaptic neuron (laminae I-III).

Principal Findings

We found that the axon of an SG EIN forms multiple functional synapses on the dendrites of a postsynaptic neuron. In many cases, EPSPs evoked by stimulating an SG EIN were sufficient to elicit spikes in a postsynaptic neuron. EPSCs were carried through both Ca²⁺-permeable (CP) and Ca²⁺-impermeable (CI) AMPA receptors (AMPARs) and showed diverse forms of functional plasticity. The synaptic efficacy could be enhanced through both activation of silent synapses and strengthening of already active synapses. We have also found that a high input resistance (R_IN, >0.5 GΩ) of the postsynaptic neuron is necessary for resolving distal dendritic EPSCs/EPSPs and correct estimation of their efficacy.

Conclusions/Significance

We conclude that the multiple synapses formed by an SG EIN on a postsynaptic neuron increase synaptic excitation and provide basis for diverse forms of plasticity. This functional organization can be important for sensory, i.e. nociceptive, processing in the spinal cord.     

Synaptic responses evoked by tactile stimuli in Purkinje cells in mouse cerebellar cortex Crus II in vivo

Background

Sensory stimuli evoke responses in cerebellar Purkinje cells (PCs) via the mossy fiber-granule cell pathway. However, the properties of synaptic responses evoked by tactile stimulation in cerebellar PCs are unknown. The present study investigated the synaptic responses of PCs in response to an air-puff stimulation on the ipsilateral whisker pad in urethane-anesthetized mice.

Methods and Main Results

Thirty-three PCs were recorded from 48 urethane-anesthetized adult (6–8-week-old) HA/ICR mice by somatic or dendritic patch-clamp recording and pharmacological methods. Tactile stimulation to the ipsilateral whisker pad was delivered by an air-puff through a 12-gauge stainless steel tube connected with a pressurized injection system. Under current-clamp conditions (I = 0), the air-puff stimulation evoked strong inhibitory postsynaptic potentials (IPSPs) in the somata of PCs. Application of SR95531, a specific GABA_A receptor antagonist, blocked IPSPs and revealed stimulation-evoked simple spike firing. Under voltage-clamp conditions, tactile stimulation evoked a sequence of transient inward currents followed by strong outward currents in the somata and dendrites in PCs. Application of SR95531 blocked outward currents and revealed excitatory postsynaptic currents (EPSCs) in somata and a temporal summation of parallel fiber EPSCs in PC dendrites. We also demonstrated that PCs respond to both the onset and offset of the air-puff stimulation.

Conclusions

These findings indicated that tactile stimulation induced asynchronous parallel fiber excitatory inputs onto the dendrites of PCs, and failed to evoke strong EPSCs and spike firing in PCs, but induced the rapid activation of strong GABA_A receptor-mediated inhibitory postsynaptic currents in the somata and dendrites of PCs in the cerebellar cortex Crus II in urethane-anesthetized mice.     

Ephrin-A5 and EphA5 Interaction Induces Synaptogenesis during Early Hippocampal Development

Background

Synaptogenesis is a fundamental step in neuronal development. For spiny glutamatergic synapses in hippocampus and cortex, synaptogenesis involves adhesion of pre and postsynaptic membranes, delivery and anchorage of pre and postsynaptic structures including scaffolds such as PSD-95 and NMDA and AMPA receptors, which are glutamate-gated ion channels, as well as the morphological maturation of spines. Although electrical activity-dependent mechanisms are established regulators of these processes, the mechanisms that function during early development, prior to the onset of electrical activity, are unclear. The Eph receptors and ephrins provide cell contact-dependent pathways that regulate axonal and dendritic development. Members of the ephrin-A family are glycosyl-phosphatidylinositol-anchored to the cell surface and activate EphA receptors, which are receptor tyrosine kinases.

Methodology/Principal Findings

Here we show that ephrin-A5 interaction with the EphA5 receptor following neuron-neuron contact during early development of hippocampus induces a complex program of synaptogenic events, including expression of functional synaptic NMDA receptor-PSD-95 complexes plus morphological spine maturation and the emergence of electrical activity. The program depends upon voltage-sensitive calcium channel Ca²⁺ fluxes that activate PKA, CaMKII and PI3 kinase, leading to CREB phosphorylation and a synaptogenic program of gene expression. AMPA receptor subunits, their scaffolds and electrical activity are not induced. Strikingly, in contrast to wild type, stimulation of hippocampal slices from P6 EphA5 receptor functional knockout mice yielded no NMDA receptor currents.

Conclusions/Significance

These studies suggest that ephrin-A5 and EphA5 signals play a necessary, activity-independent role in the initiation of the early phases of synaptogenesis. The coordinated expression of the NMDAR and PSD-95 induced by eprhin-A5 interaction with EphA5 receptors may be the developmental switch that induces expression of AMPAR and their interacting proteins and the transition to activity-dependent synaptic regulation.     

Long-Term Plasticity Is Proportional to Theta-Activity

Background

Theta rhythm in the hippocampal formation is a main feature of exploratory behaviour and is believed to enable the encoding of new spatial information and the modification of synaptic weights. Cyclic changes of dentate gyrus excitability during theta rhythm are related to its function, but whether theta epochs per se are able to alter network properties of dentate gyrus for long time-periods is still poorly understood.

Methodology/Principal Findings

We used low-frequency stimulation protocols that amplify the power of endogenous theta oscillations, in order to estimate the plasticity effect of endogenous theta oscillations on a population level. We found that stimulation-induced augmentation of the theta rhythm is linked to a subsequent increase of neuronal excitability and decrease of the synaptic response. This EPSP-to-Spike uncoupling is related to an increased postsynaptic spiking on the positive phases of theta frequency oscillations. Parallel increase of the field EPSP slope and the population spike occurs only after concurrent pre- and postsynaptic activation. Furthermore, we observed that long-term potentiation (>24 h) occurs in the dentate gyrus of freely behaving adult rats after phasic activity of entorhinal afferents in the theta-frequency range. This plasticity is proportional to the field bursting activity of granule cells during the stimulation, and may comprise a key step in spatial information transfer. Long-term potentiation of the synaptic component occurs only when the afferent stimulus precedes the evoked population burst, and is input-specific.

Conclusions/Significance

Our data confirm the role of the dentate gyrus in filtering information to the subsequent network during the activated state of the hippocampus.     

Temporal Control of Immediate Early Gene Induction by Light

Background

The light-gated cation channel channelrhodopsin-2 (ChR2) is a powerful tool for the optical induction of action potentials in neurons. Mutations of the cysteine 128 (C128) residue have been shown to greatly extend the lifetime of the conducting state of ChR2. However, until now, only subthreshold depolarizations have been reported from C128 mutants.

Methods and Findings

Here we report the induction of long high-frequency spike trains by brief light pulses in ChR2(C128A)-transfected pyramidal cells in hippocampal slice culture. ChR2(C128A)-mediated spike bursts triggered expression of the immediate early gene c-fos in pyramidal neurons. Robust and cell-specific expression of c-Fos protein was detected after a single blue light pulse and depended on action potential firing, but not on synaptic activity. However, photocurrents diminished upon repeated stimulation and limited the number of action potential bursts that could be elicited.

Conclusions

We conclude that the C128A mutant is not suitable for chronic stimulation of neurons, but very useful for light-controlled induction of immediate early genes. This property of ChR2(C128A) could be harnessed to control the expression of proteins under control of the c-fos promoter with precise timing and single cell specificity.     

Natural Spike Trains Trigger Short- and Long-Lasting Dynamics at Hippocampal Mossy Fiber Synapses in Rodents

Background

Synapses exhibit strikingly different forms of plasticity over a wide range of time scales, from milliseconds to hours. Studies on synaptic plasticity typically use constant-frequency stimulation to activate synapses, whereas in vivo activity of neurons is irregular.

Methodology/Principal Findings

Using extracellular and whole-cell electrophysiological recordings, we have here studied the synaptic responses at hippocampal mossy fiber synapses in vitro to stimulus patterns obtained from in vivo recordings of place cell firing of dentate gyrus granule cells in behaving rodents. We find that synaptic strength is strongly modulated on short- and long-lasting time scales during the presentation of the natural stimulus trains.

Conclusions/Significance

We conclude that dynamic short- and long-term synaptic plasticity at the hippocampal mossy fiber synapse plays a prominent role in normal synaptic function.     

Brain deletion of insulin receptor substrate 2 disrupts hippocampal synaptic plasticity and metaplasticity

Objective

Diabetes mellitus is associated with cognitive deficits and an increased risk of dementia, particularly in the elderly. These deficits and the corresponding neurophysiological structural and functional alterations are linked to both metabolic and vascular changes, related to chronic hyperglycaemia, but probably also defects in insulin action in the brain. To elucidate the specific role of brain insulin signalling in neuronal functions that are relevant for cognitive processes we have investigated the behaviour of neurons and synaptic plasticity in the hippocampus of mice lacking the insulin receptor substrate protein 2 (IRS-2).

Research Design and Methods

To study neuronal function and synaptic plasticity in the absence of confounding factors such as hyperglycaemia, we used a mouse model with a central nervous system- (CNS)-restricted deletion of IRS-2 (NesCreIrs2KO).

Results

We report a deficit in NMDA receptor-dependent synaptic plasticity in the hippocampus of NesCreIrs2KO mice, with a concomitant loss of metaplasticity, the modulation of synaptic plasticity by the previous activity of a synapse. These plasticity changes are associated with reduced basal phosphorylation of the NMDA receptor subunit NR1 and of downstream targets of the PI3K pathway, the protein kinases Akt and GSK-3β.

Conclusions

These findings reveal molecular and cellular mechanisms that might underlie cognitive deficits linked to specific defects of neuronal insulin signalling.     

Netrin signaling breaks the equivalence between two identified zebrafish motoneurons revealing a new role of intermediate targets

Background

We previously showed that equivalence between two identified zebrafish motoneurons is broken by interactions with identified muscle fibers that act as an intermediate target for the axons of these motoneurons. Here we investigate the molecular basis of the signaling interaction between the intermediate target and the motoneurons.

Principal Findings

We provide evidence that Netrin 1a is an intermediate target-derived signal that causes two equivalent motoneurons to adopt distinct fates. We show that although these two motoneurons express the same Netrin receptors, their axons respond differently to Netrin 1a encountered at the intermediate target. Furthermore, we demonstrate that when Netrin 1a is knocked down, more distal intermediate targets that express other Netrins can also function to break equivalence between these motoneurons.

Significance

Our results suggest a new role for intermediate targets in breaking neuronal equivalence. The data we present reveal that signals encountered during axon pathfinding can cause equivalent neurons to adopt distinct fates. Such signals may be key in diversifying a neuronal population and leading to correct circuit formation.     

Brief Subthreshold Events Can Act as Hebbian Signals for Long-Term Plasticity

Background

Action potentials are thought to be determinant for the induction of long-term synaptic plasticity, the cellular basis of learning and memory. However, neuronal activity does not lead systematically to an action potential but also, in many cases, to synaptic depolarizing subthreshold events. This is particularly exemplified in corticostriatal information processing. Indeed, the striatum integrates information from the whole cerebral cortex and, due to the membrane properties of striatal medium spiny neurons, cortical inputs do not systematically trigger an action potential but a wide range of subthreshold postsynaptic depolarizations. Accordingly, we have addressed the following question: does a brief subthreshold event act as a Hebbian signal and induce long-term synaptic efficacy changes?

Methodology/Principal Findings

Here, using perforated patch-clamp recordings on rat brain corticostriatal slices, we demonstrate, that brief (30 ms) subthreshold depolarizing events in quasi-coincidence with presynaptic activity can act as Hebbian signals and are sufficient to induce long-term synaptic plasticity at corticostriatal synapses. This “subthreshold-depolarization dependent plasticity” (SDDP) induces strong, significant and bidirectional long-term synaptic efficacy changes at a very high occurrence (81%) for time intervals between pre- and postsynaptic stimulations (Δt) of −110<Δt<+110 ms. Such subthreshold depolarizations are able to induce robust long-term depression (cannabinoid type-1 receptor-activation dependent) as well as long-term potentiation (NMDA receptor-activation dependent).

Conclusion/Significance

Our data show the existence of a robust, reliable and timing-dependent bidirectional long-term plasticity induced by brief subthreshold events paired with presynaptic activity. The existence of a subthreshold-depolarization dependent plasticity extends considerably, beyond the action potential, the neuron''s capabilities to express long-term synaptic efficacy changes.