The nature of the synaptic connection from the auditory nerve onto the cochlear nucleus neurons has a profound impact on how sound information is transmitted. Short-term synaptic plasticity, by dynamically modulating synaptic strength, filters information contained in the firing patterns. In the sound-localization circuits of the brain stem, the synapses of the timing pathway are characterized by strong short-term depression. We investigated the short-term synaptic plasticity of the inputs to the bird’s cochlear nucleus angularis (NA), which encodes intensity information, by using chick embryonic brain slices and trains of electrical stimulation. These excitatory inputs expressed a mixture of short-term facilitation and depression, unlike those in the timing nuclei that only depressed. Facilitation and depression at NA synapses were balanced such that postsynaptic response amplitude was often maintained throughout the train at high firing rates (>100 Hz). The steady-state input rate relationship of the balanced synapses linearly conveyed rate information and therefore transmits intensity information encoded as a rate code in the nerve. A quantitative model of synaptic transmission could account for the plasticity by including facilitation of release (with a time constant of ~40 ms), and a two-step recovery from depression (with one slow time constant of ~8 s, and one fast time constant of ~20 ms). A simulation using the model fit to NA synapses and auditory nerve spike trains from recordings in vivo confirmed that these synapses can convey intensity information contained in natural train inputs.
Alterations in synaptic strength over short time scales, termed short-term synaptic plasticity, can gate the flow of information through neural circuits. Different information can be extracted from the same presynaptic spike train depending on the activity- and time-dependent properties of the plasticity at a given synapse. The parallel processing in the brain stem auditory pathways provides an excellent model system for investigating the functional implications of short-term plasticity in neural coding. We review recent evidence that short-term plasticity differs in different pathways with a special emphasis on the ‘intensity’ pathway. While short-term depression dominates the ‘timing’ pathway, the intensity pathway is characterized by a balance of short-term depression and facilitation that allows linear transmission of rate-coded intensity information. Target-specific regulation of presynaptic plasticity mechanisms underlies the differential expression of depression and facilitation. The potential contribution of short-term plasticity to different aspects of ‘intensity’-related information processing, such as interaural level/intensity difference coding, amplitude modulation coding, and intensity-dependent gain control coding, is discussed.
Identification of shared features between avian and mammalian auditory brainstem circuits has provided much insight into the mechanisms underlying early auditory processing. However, previous studies have highlighted an apparent difference in inhibitory systems; synaptic inhibition is thought to be slow and GABAergic in birds, but to have fast kinetics and be predominantly glycinergic in mammals. Using patch-clamp recordings in chick brainstem slices, we found this distinction is not exclusively true. Consistent with previous work, inhibitory postsynaptic currents (IPSCs) in nucleus magnocellularis (NM) were slow and mediated by GABAA receptors. However, IPSCs in nucleus laminaris (NL) and a subset of neurons in nucleus angularis (NA) had rapid time courses two to three-fold faster than those in NM. Further, we found IPSCs in NA were mediated by both glycine and GABAA receptors, demonstrating for the first time a role for fast glycinergic transmission in the avian auditory brainstem. Although NM, NL and NA have unique roles in auditory processing, the majority of inhibitory input to each nucleus arises from the same source, ipsilateral superior olivary nucleus (SON). Our results demonstrate remarkable diversity of inhibitory transmission among the avian brainstem nuclei and suggest differential glycine and GABAA receptor activity tailors inhibition to the specific functional roles of NM, NL, and NA despite common SON input. We additionally observed that glycinergic/GABAergic activity in NA was usually depolarizing and could elicit spiking activity in NA neurons. Because NA projects to SON, these excitatory effects may influence the recruitment of inhibitory activity in the brainstem nuclei.
Auditory; GABA; Glycine; Patch Clamp; Inhibition; Synapse
Synapses formed by one cell type onto another cell type tend to show characteristic short-term plasticity, which varies from facilitating to depressing depending on the particular system. Within a population of synapses, plasticity can also be variable, and it is unknown how this plasticity is determined on a cell-by-cell level. We have investigated this in the mouse cochlear nucleus, where auditory nerve (AN) fibers contact bushy cells (BCs) at synapses called “endbulbs of Held”. Synapses formed by different AN fibers onto one BC had plasticity that was more similar than would be expected at random. Experiments using MK-801 indicated that this resulted in part from similarity in the presynaptic probability of release. This similarity was not present in immature synapses, but emerged after the onset of hearing. In addition, this phenomenon also occurred at excitatory synapses in the cerebellum. This indicates that postsynaptic cells coordinate the plasticity of their inputs, which suggests that plasticity is of fundamental importance to synaptic function.
The brainstem auditory pathway is obligatory for all aural information. Brainstem auditory neurons must encode the level and timing of sounds, as well as their time-dependent spectral properties, the fine structure and envelope, which are essential for sound discrimination. This study focused on envelope coding in the two cochlear nuclei of the barn owl, nucleus angularis (NA) and nucleus magnocellularis (NM). NA and NM receive input from bifurcating auditory nerve fibers and initiate processing pathways specialized in encoding interaural time (ITD) and level (ILD) differences, respectively. We found that NA neurons, though unable to accurately encode stimulus phase, lock more strongly to the stimulus envelope than NM units. The spectrotemporal receptive fields (STRFs) of NA neurons exhibit a pre-excitatory suppressive field. Using multilinear regression analysis and computational modeling, we show that this feature of STRFs can account for enhanced across-trial response reliability, by locking spikes to the stimulus envelope. Our findings indicate a dichotomy in envelope coding between the time and intensity processing pathways as early as at the level of the cochlear nuclei. This allows the ILD processing pathway to encode envelope information with greater fidelity than the ITD processing pathway. Furthermore, we demonstrate that the properties of the neurons’ STRFs can be quantitatively related to spike timing reliability.
Nucleus angularis; STRF; spectrotemporal tuning; cochlear nuclei; barn owl; response reliability
Neurons in many brain regions release endocannabinoids from their dendrites that act as retrograde signals to transiently suppress neurotransmitter release from presynaptic terminals. Little is known however about the physiological mechanisms of short-term endocannabinoid-mediated plasticity under physiological conditions. Here we investigate calcium-dependent endocannabinoid release from cartwheel cells (CWCs) of the mouse dorsal cochlear nucleus (DCN) in the auditory brainstem that provide feedforward inhibition onto DCN principal neurons. We report that sustained action potential firing by CWCs evokes endocannabinoid release in response to submicromolar elevation of dendritic calcium that transiently suppresses their parallel fiber inputs by >70%. Basal spontaneous CWC firing rates are insufficient to evoke tonic suppression of PF synapses. However, elevating CWC firing rates by stimulation of parallel fibers triggers release of endocannabinoids and heterosynaptic suppression of PF inputs. Spike-evoked suppression by endocannabinoids selectively suppresses excitatory synapses but glycinergic/GABAergic inputs onto CWCs are not affected. Our findings demonstrate a mechanism of transient plasticity mediated by endocannabinoids that heterosynaptically suppresses subsets of excitatory presynaptic inputs to CWCs that regulates feedforward inhibition of DCN principal neurons and may thereby influence the output of the DCN.
dorsal cochlear nucleus; cartwheel cell; endocannabinoids; synaptic plasticity; calcium imaging
Fast, temporally-precise, and consistent synaptic transmission is required to encode features of acoustic stimuli. Neurons of nucleus magnocellularis (NM) in the auditory brain stem of the chick possess numerous adaptations to optimize the coding of temporal information. One potential problem for the system is the depression of synaptic transmission during a prolonged stimulus. The present studies tested the hypothesis that cannabinoid receptor one (CB1) signaling may limit synaptic depression at the auditory nerve-NM synapse. In situ hybridization was used to confirm that CB1 mRNA is expressed in the cochlear ganglion; immunohistochemistry was used to confirm the presence of CB1 protein in NM. These findings are consistent with the common presynaptic locus of CB1 in the brain. Rate-dependent synaptic depression was then examined in a brain slice preparation before and after administration of WIN 55,212-2 (WIN), a potent CB1 agonist. WIN decreased the amplitude of excitatory postsynaptic currents and also reduced depression across a train of stimuli. The effect was most obvious late in the pulse train and during high rates of stimulation. This CB1-mediated influence could allow for lower, but more consistent activation of NM neurons, which could be of importance for optimizing the coding of prolonged, temporally-locked acoustic stimuli.
cochlear nucleus; synaptic depression; nucleus magnocellularis; brain slice; WIN 55,212-2; calyx
There is a growing appreciation of synaptic plasticity in the early levels of auditory processing, and particularly of its role in inhibitory circuits. Synaptic strength in auditory brainstem and midbrain is sensitive to standard protocols for induction of long-term depression, potentiation, and spike-timing-dependent plasticity. Differential forms of plasticity are operative at synapses onto inhibitory versus excitatory neurons within a circuit, and together these could serve to tune circuits involved in sound localization or multisensory integration. Such activity-dependent control of synaptic function in inhibitory neurons may also be expressed after hearing loss and could underlie persistent neuronal activity in patients with tinnitus.
Short-term presynaptic plasticity designates variations of the amplitude of synaptic information transfer whereby the amount of neurotransmitter released upon presynaptic stimulation changes over seconds as a function of the neuronal firing activity. While a consensus has emerged that the resulting decrease (depression) and/or increase (facilitation) of the synapse strength are crucial to neuronal computations, their modes of expression in vivo remain unclear. Recent experimental studies have reported that glial cells, particularly astrocytes in the hippocampus, are able to modulate short-term plasticity but the mechanism of such a modulation is poorly understood. Here, we investigate the characteristics of short-term plasticity modulation by astrocytes using a biophysically realistic computational model. Mean-field analysis of the model, supported by intensive numerical simulations, unravels that astrocytes may mediate counterintuitive effects. Depending on the expressed presynaptic signaling pathways, astrocytes may globally inhibit or potentiate the synapse: the amount of released neurotransmitter in the presence of the astrocyte is transiently smaller or larger than in its absence. But this global effect usually coexists with the opposite local effect on paired pulses: with release-decreasing astrocytes most paired pulses become facilitated, namely the amount of neurotransmitter released upon spike i+1 is larger than that at spike i, while paired-pulse depression becomes prominent under release-increasing astrocytes. Moreover, we show that the frequency of astrocytic intracellular Ca2+ oscillations controls the effects of the astrocyte on short-term synaptic plasticity. Our model explains several experimental observations yet unsolved, and uncovers astrocytic gliotransmission as a possible transient switch between short-term paired-pulse depression and facilitation. This possibility has deep implications on the processing of neuronal spikes and resulting information transfer at synapses.
Synaptic plasticity is the capacity of a preexisting connection between two neurons to change in strength as a function of neuronal activity. Because it admittedly underlies learning and memory, the elucidation of its constituting mechanisms is of crucial importance in many aspects of normal and pathological brain function. Short-term presynaptic plasticity refers to changes occurring over short time scales (milliseconds to seconds) that are mediated by frequency-dependent modifications of the amount of neurotransmitter released by presynaptic stimulation. Recent experiments have reported that glial cells, especially hippocampal astrocytes, can modulate short-term plasticity, but the mechanism of such modulation is poorly understood. Here, we explore a plausible form of modulation of short-term plasticity by astrocytes using a biophysically realistic computational model. Our analysis indicates that astrocytes could simultaneously affect synaptic release in two ways. First, they either decrease or increase the overall synaptic release of neurotransmitter. Second, for stimuli that are delivered as pairs within short intervals, they systematically increase or decrease the synaptic response to the second one. Hence, our model suggests that astrocytes could transiently trigger switches between paired-pulse depression and facilitation. This property explains several challenging experimental observations and has a deep impact on our understanding of synaptic information transfer.
The acoustic environment contains biologically relevant information on time scales from microseconds to tens of seconds. The auditory brainstem nuclei process this temporal information through parallel pathways that originate in the cochlear nucleus from different classes of cells. While the roles of ion channels and excitatory synapses in temporal processing have been well studied, the contribution of inhibition is less well understood. Here, we show in CBA/CaJ mice that the two major projection neurons of the ventral cochlear nucleus, the bushy and T-stellate cells, receive glycinergic inhibition with different synaptic conductance time courses. Bushy cells, which provide precisely timed spike trains used in sound localization and pitch identification, receive slow inhibitory inputs. In contrast, T-stellate cells, which encode slower envelope information, receive inhibition that is eight-fold faster. Both types of inhibition improved the precision of spike timing, but engage different cellular mechanisms and operate on different time scales. Computer models reveal that slow IPSCs in bushy cells can improve spike timing on the scale of tens of microseconds. While fast and slow IPSCs in T-stellate cells improve spike timing on the scale of milliseconds, only fast IPSCs can enhance the detection of narrowband acoustic signals in a complex background. Our results suggest that target-specific IPSC kinetics are critical for the segregated parallel processing of temporal information from the sensory environment.
Spike-timing dependent plasticity (STDP), a widespread synaptic modification mechanism, is sensitive to correlations between presynaptic spike trains and it generates competition among synapses. However, STDP has an inherent instability because strong synapses are more likely to be strengthened than weak ones, causing them to grow in strength until some biophysical limit is reached. Through simulations and analytic calculations, we show that a small temporal shift in the STDP window that causes synchronous, or nearly synchronous, pre- and postsynaptic action potentials to induce long-term depression can stabilize synaptic strengths. Shifted STDP also stabilizes the postsynaptic firing rate and can implement both Hebbian and anti-Hebbian forms of competitive synaptic plasticity. Interestingly, the overall level of inhibition determines whether plasticity is Hebbian or anti-Hebbian. Even a random symmetric jitter of a few milliseconds in the STDP window can stabilize synaptic strengths while retaining these features. The same results hold for a shifted version of the more recent “triplet” model of STDP. Our results indicate that the detailed shape of the STDP window function near the transition from depression to potentiation is of the utmost importance in determining the consequences of STDP, suggesting that this region warrants further experimental study.
Synaptic plasticity is believed to be a fundamental mechanism of learning and memory. In spike-timing dependent synaptic plasticity (STDP), the temporal order of pre- and postsynaptic spiking across a synapse determines whether it is strengthened or weakened. STDP can induce competition between the different inputs synapsing onto a neuron, which is crucial for the formation of functional neuronal circuits. However, strong synaptic competition is often incompatible with inherent synaptic stability. Synaptic modification by STDP is controlled by a so-called temporal window function that determines how synaptic modification depends on spike timing. We show that a small shift, or random jitter, in the conventional temporal window function used for STDP that is compatible with the underlying molecular kinetics of STDP, can both stabilize synapses and maintain competition. The outcome of the competition is determined by the level of inhibitory input to the postsynaptic neuron. We conclude that the detailed shape of the temporal window function is critical in determining the functional consequences of STDP and thus deserves further experimental study.
Depletion of synaptic neurotransmitter vesicles induces a form of short term depression in synapses throughout the nervous system. This plasticity affects how synapses filter presynaptic spike trains. The filtering properties of short term depression are often studied using a deterministic synapse model that predicts the mean synaptic response to a presynaptic spike train, but ignores variability introduced by the probabilistic nature of vesicle release and stochasticity in synaptic recovery time. We show that this additional variability has important consequences for the synaptic filtering of presynaptic information. In particular, a synapse model with stochastic vesicle dynamics suppresses information encoded at lower frequencies more than information encoded at higher frequencies, while a model that ignores this stochasticity transfers information encoded at any frequency equally well. This distinction between the two models persists even when large numbers of synaptic contacts are considered. Our study provides strong evidence that the stochastic nature neurotransmitter vesicle dynamics must be considered when analyzing the information flow across a synapse.
Neurons communicate through electro-chemical connections called synapses. Action potentials in a presynaptic neuron cause neurotransmitter vesicles to release their contents which then bind to nearby receptors on a postsynaptic neuron's membrane, transiently altering its conductance. After it is released, the replacement of a neurotransmitter vesicle takes time and the depletion of vesicles can prevent subsequent action potentials from eliciting a postsynaptic response, an effect that represents a form of short term synaptic depression. When a vesicle is available for release, an action potential elicits its release probabilistically and depleted vesicles are replenished randomly in time, making the transmission of presynaptic signals inherently unreliable. We analyze a mathematical model of vesicle release and recovery to understand how signals encoded in sequences of presynaptic action potentials are reflected in the fluctuations of a postsynaptic neuron's conductance. We find that slow modulations in the rate of presynaptic action potentials are more difficult for a postsynaptic neuron to detect than faster modulations. This phenomenon is only observed when randomness in vesicle release and replacement is taken into account. Thus, by including stochasticity in the workings of synaptic dynamics we give new qualitative understanding to how information is transferred in the nervous system.
The nervous system must dynamically represent sensory information in order for animals to perceive and operate within a complex, changing environment. Receptive field plasticity in the auditory cortex allows cortical networks to organize around salient features of the sensory environment during postnatal development, and then subsequently refine these representations depending on behavioral context later in life. Here we review the major features of auditory cortical receptive field plasticity in young and adult animals, focusing on modifications to frequency tuning of synaptic inputs. Alteration in the patterns of acoustic input, including sensory deprivation and tonal exposure, leads to rapid adjustments of excitatory and inhibitory strengths that collectively determine the suprathreshold tuning curves of cortical neurons. Long-term cortical plasticity also requires co-activation of subcortical neuromodulatory control nuclei such as the cholinergic nucleus basalis, particularly in adults. Regardless of developmental stage, regulation of inhibition seems to be a general mechanism by which changes in sensory experience and neuromodulatory state can remodel cortical receptive fields. We discuss recent findings suggesting that the microdynamics of synaptic receptive field plasticity unfold as a multi-phase set of distinct phenomena, initiated by disrupting the balance between excitation and inhibition, and eventually leading to wide-scale changes to many synapses throughout the cortex. These changes are coordinated to enhance the representations of newly-significant stimuli, possibly for improved signal processing and language learning in humans.
auditory cortex; development; excitatory-inhibitory balance; hearing loss; neuromodulation; receptive field; synaptic plasticity
Tinnitus is the persistent perception of a subjective sound. Tinnitus is almost universally experienced in some forms. In most cases, recovery may occur in seconds, hours, or days. How does tinnitus shift from a transient condition to a lifelong disorder? Several lines of evidence, including clinical studies and animal models, indicate that the brain, rather than the inner ear, may in some cases be the site of maintenance of tinnitus. One hypothesis is that normal electrical activity in the auditory system becomes pathologically persistent due to plasticity-like mechanisms that can lead to long-term changes in the communication between neurons. A candidate site for the expression of this so-called synaptic plasticity is a region of the brainstem called the dorsal cochlear nucleus (DCN), a site of integration of acoustic and multimodal, sensory inputs.
Here we review recent findings on cellular mechanisms observed in the DCN that can lead to long-term changes in the synaptic strength between different neurons in the DCN. These cellular mechanisms could provide candidate signaling pathways underlying the induction (ignition) and/or the expression (maintenance) of tinnitus.
synaptic plasticity; dorsal cochlear nucleus; tinnitus; auditory neuroscience
Synapses may undergo long-term increases or decreases in synaptic strength dependent on critical differences in the timing between pre- and postsynaptic activity. Such spike-timing-dependent plasticity (STDP) follows rules that govern how patterns of neural activity induce changes in synaptic strength. Synaptic plasticity in the dorsal cochlear nucleus (DCN) follows Hebbian and anti-Hebbian patterns in a cell-specific manner. Here we show that these opposing responses to synaptic activity result from differential expression of two signaling pathways. Ca2+/calmodulin-dependent protein kinase II (CaMKII) signaling underlies Hebbian postsynaptic LTP in principal cells. By contrast, in interneurons, a temporally precise anti-Hebbian synaptic spike-timing rule results from the combined effects of postsynaptic CaMKII–dependent LTP and endocannabinoid-dependent presynaptic LTD. Cell specificity in the circuit arises from selective targeting of presynaptic CB1 receptors in different axonal terminals. Hence, pre- and postsynaptic sites of expression determine both the sign and timing requirements of long-term plasticity in interneurons.
A hallmark of brain organization is the integration of primary and modulatory pathways by principal neurons. Primary sensory inputs are usually not plastic, while modulatory inputs converging to the same principal neuron can be plastic. However, the mechanisms determining this input specific expression of synaptic plasticity remain unknown. We investigated this problem in the dorsal cochlear nucleus (DCN), where principal cells integrate primary auditory nerve input with plastic, parallel fiber input. Our previous DCN studies have shown that parallel fiber inputs exhibit short- and long-term plasticities mediated by endocannabinoid signaling. Here we show that auditory nerve inputs to principal cells do not show short- or long-term endocannabinoid-mediated synaptic plasticity. Electrophysiological and electron microscopy studies indicate that input specificity arises from selective expression of presynaptic cannabinoid (CB1) receptors in parallel fiber terminals, but not in auditory nerve terminals. However, pairing of parallel fiber activity with auditory nerve activity elicits plasticity in parallel fiber inputs, thus suggesting a role for synaptic plasticity in multisensory integration.
endocannabinoids; dorsal cochlear nucleus; plasticity; electron microscopy; electrophysiology
One important model for understanding neuronal computation is how auditory information is transformed at the synapses made by auditory nerve (AN) fibers on the bushy cells (BCs) in the anteroventral cochlear nucleus (AVCN). This transformation is influenced by synaptic plasticity, the mechanisms of which have been studied primarily using postsynaptic electrophysiology. However, it is also important to make direct measurements of the presynaptic terminal to consider presynaptic mechanisms. Here we introduce a technique for doing that using calcium imaging of presynaptic AN terminals, by injecting dextran-conjugated fluorophores into the cochlea. To measure the calcium transients, we used calcium-sensitive fluorophores, and measured the changes in fluorescence upon stimulation. As an example of the application of this technique, we showed that activation of GABAB receptors reduces presynaptic calcium influx. This technique could be further extended to study the effects of activity- and other neuromodulator-dependent plasticities on AN terminals.
endbulb; calcium imaging; auditory nerve; bushy cell
Functional inhibitory synapses form in auditory cortex well before the onset of normal hearing. However, their properties change dramatically during normal development, and many of these maturational events are delayed by hearing loss. Here, we review recent findings on the developmental plasticity of inhibitory synapse strength, kinetics, and GABAA receptor localization in auditory cortex. Although hearing loss generally leads to a reduction of inhibitory strength, this depends on the type of presynaptic interneuron. Furthermore, plasticity of inhibitory synapses also depends on the postsynaptic target. Hearing loss leads reduced GABAA receptor localization to the membrane of excitatory, but not inhibitory neurons. A reduction in normal activity in development can also affect the use-dependent plasticity of inhibitory synapses. Even moderate hearing loss can disrupt inhibitory short- and long-term synaptic plasticity. Thus, the cortex did not compensate for the loss of inhibition in the brainstem, but rather exacerbated the response to hearing loss by further reducing inhibitory drive. Together, these results demonstrate that inhibitory synapses are exceptionally dynamic during development, and deafness-induced perturbation of inhibitory properties may have a profound impact on auditory processing.
development; deafness; inhibitory interneuron; short-term depression; long-term potentiation; auditory cortex
The hippocampus plays a central role in memory formation in the mammalian brain. Its ability to encode information is thought to depend on the plasticity of synaptic connections between neurons. In the pyramidal neurons constituting the primary hippocampal output to the cortex, located in area CA1, firing of presynaptic CA3 pyramidal neurons produces monosynaptic excitatory postsynaptic potentials (EPSPs) followed rapidly by feedforward (disynaptic) inhibitory postsynaptic potentials (IPSPs). Long-term potentiation (LTP) of the monosynaptic glutamatergic inputs has become the leading model of synaptic plasticity, in part due to its dependence on NMDA receptors (NMDARs), required for spatial and temporal learning in intact animals. Using whole-cell recording in hippocampal slices from adult rats, we find that the efficacy of synaptic transmission from CA3 to CA1 can be enhanced without the induction of classic LTP at the glutamatergic inputs. Taking care not to directly stimulate inhibitory fibers, we show that the induction of GABAergic plasticity at feedforward inhibitory inputs results in the reduced shunting of excitatory currents, producing a long-term increase in the amplitude of Schaffer collateral-mediated postsynaptic potentials. Like classic LTP, disinhibition-mediated LTP requires NMDAR activation, suggesting a role in types of learning and memory attributed primarily to the former and raising the possibility of a previously unrecognized target for therapeutic intervention in disorders linked to memory deficits, as well as a potentially overlooked site of LTP expression in other areas of the brain.
Experimental studies have observed Long Term synaptic Potentiation (LTP) when a presynaptic neuron fires shortly before a postsynaptic neuron, and Long Term Depression (LTD) when the presynaptic neuron fires shortly after, a phenomenon known as Spike Timing Dependant Plasticity (STDP). When a neuron is presented successively with discrete volleys of input spikes STDP has been shown to learn ‘early spike patterns’, that is to concentrate synaptic weights on afferents that consistently fire early, with the result that the postsynaptic spike latency decreases, until it reaches a minimal and stable value. Here, we show that these results still stand in a continuous regime where afferents fire continuously with a constant population rate. As such, STDP is able to solve a very difficult computational problem: to localize a repeating spatio-temporal spike pattern embedded in equally dense ‘distractor’ spike trains. STDP thus enables some form of temporal coding, even in the absence of an explicit time reference. Given that the mechanism exposed here is simple and cheap it is hard to believe that the brain did not evolve to use it.
Spike-timing-dependent plasticity (STDP) provides a cellular implementation of the Hebb postulate, which states that synapses, whose activity repeatedly drives action potential firing in target cells, are potentiated. At glutamatergic synapses onto hippocampal and neocortical pyramidal cells, synaptic activation followed by spike firing in the target cell causes long-term potentiation (LTP)—as predicted by Hebb—whereas excitatory postsynaptic potentials (EPSPs) evoked after a spike elicit long-term depression (LTD)—a phenomenon that was not specifically addressed by Hebb. In both instances the action potential in the postsynaptic target neuron is an instructive signal that is capable of supporting synaptic plasticity. STDP generally relies on the propagation of Na+ action potentials that are initiated in the axon hillhock back into the dendrite, where they cause depolarization and boost local calcium influx. However, recent studies in CA1 hippocampal pyramidal neurons have suggested that local calcium spikes might provide a more efficient trigger for LTP induction than backpropagating action potentials. Dendritic calcium spikes also play a role in an entirely different type of STDP that can be observed in cerebellar Purkinje cells. These neurons lack backpropagating Na+ spikes. Instead, plasticity at parallel fiber (PF) to Purkinje cell synapses depends on the relative timing of PF-EPSPs and activation of the glutamatergic climbing fiber (CF) input that causes dendritic calcium spikes. Thus, the instructive signal in this system is externalized. Importantly when EPSPs are elicited before CF activity, PF-LTD is induced rather than LTP. Thus, STDP in the cerebellum follows a timing rule that is opposite to its hippocampal/neocortical counterparts. Regardless, a common motif in plasticity is that LTD/LTP induction depends on the relative timing of synaptic activity and regenerative dendritic spikes which are driven by the instructive signal.
calcium; climbing fiber; dendrite; long-term depression; long-term potentiation; parallel fiber; Purkinje cell; pyramidal cell
Input specific long-term potentiation (LTP) in afferent inputs to the amygdala serves an essential function in the acquisition of fear memory. Factors underlying input specificity of synaptic modifications implicated in information transfer in fear conditioning pathways remain unknown. Here we show that the strength of naïve synapses in two auditory inputs converging on a single neuron in the lateral nucleus of the amygdala is only modified when a postsynaptic action potential closely follows a synaptic response. The stronger inhibitory drive in thalamic pathway, as compared to cortical input, hampers the induction of LTP at thalamo-amygdala synapses, contributing to the spatial specificity of LTP in convergent inputs. These results indicate that spike timing-dependent synaptic plasticity in afferent projections to the LA is both temporarily and spatially asymmetric, thus providing a mechanism for the conditioned stimulus discrimination during fear behavior.
Vestibulo-ocular reflex (VOR) gain adaptation, a longstanding experimental model of cerebellar learning, utilizes sites of plasticity in both cerebellar cortex and brainstem. However, the mechanisms by which the activity of cortical Purkinje cells may guide synaptic plasticity in brainstem vestibular neurons are unclear. Theoretical analyses indicate that vestibular plasticity should depend upon the correlation between Purkinje cell and vestibular afferent inputs, so that, in gain-down learning for example, increased cortical activity should induce long-term depression (LTD) at vestibular synapses.
Here we expressed this correlational learning rule in its simplest form, as an anti-Hebbian, heterosynaptic spike-timing dependent plasticity interaction between excitatory (vestibular) and inhibitory (floccular) inputs converging on medial vestibular nucleus (MVN) neurons (input-spike-timing dependent plasticity, iSTDP). To test this rule, we stimulated vestibular afferents to evoke EPSCs in rat MVN neurons in vitro. Control EPSC recordings were followed by an induction protocol where membrane hyperpolarizing pulses, mimicking IPSPs evoked by flocculus inputs, were paired with single vestibular nerve stimuli. A robust LTD developed at vestibular synapses when the afferent EPSPs coincided with membrane hyperpolarisation, while EPSPs occurring before or after the simulated IPSPs induced no lasting change. Furthermore, the iSTDP rule also successfully predicted the effects of a complex protocol using EPSP trains designed to mimic classical conditioning.
These results, in strong support of theoretical predictions, suggest that the cerebellum alters the strength of vestibular synapses on MVN neurons through hetero-synaptic, anti-Hebbian iSTDP. Since the iSTDP rule does not depend on post-synaptic firing, it suggests a possible mechanism for VOR adaptation without compromising gaze-holding and VOR performance in vivo.
Several mechanisms can underlie short-term synaptic depression, including vesicle depletion, receptor desensitization, and changes in presynaptic release probability. To determine which mechanisms affect depression under physiological conditions, we studied the synapse formed by auditory nerve fibers onto bushy cells in the anteroventral cochlear nucleus (the “endbulb of Held”) using voltage-clamp recordings of brain slices from P15–21 mice near physiological temperatures. Depression of both AMPA and NMDA EPSCs showed two phases of recovery. The fast component of depression for the AMPA EPSC was eliminated by cyclothiazide and aniracetam, suggesting it results from desensitization. The fast component of depression for the NMDA EPSC was reduced by the low-affinity antagonist L-AP5, suggesting it results from saturation. The remaining depression in AMPA and NMDA components is identical and therefore presynaptic in origin. It is likely to result from presynaptic vesicle depletion. Recovery from depression after trains of activity was slowed by the application of EGTA-AM, suggesting that the endbulb has a residual-calcium-dependent form of recovery. We developed a model that incorporates depletion, desensitization, and calcium-dependent recovery. This model replicated experimental findings over a range of experimental conditions. The model further indicated that desensitization plays only a minor role during prolonged activity, in large part because presynaptic release is so depleted. Thus, depletion appears to be the dominant mechanism of depression at the endbulb during normal activity. Furthermore, calcium-dependent recovery at the endbulb is critical to prevent complete run-down during high activity and to preserve the reliability of information transmission.
Synapse; Depression; Saturation; Desensitization; Endbulb; Modeling
Visual and somatosensory cortices exhibit profound experience-dependent plasticity during development and adulthood and are common model systems for probing the synaptic and molecular mechanisms of plasticity. However, comparisons between the two areas may be confounded by a lack of accurate information on their relative rates of development. In this study, we used whole cell recording in acute brain slices to study synaptic development in mouse barrel and visual cortex. We found that short-term plasticity (STP) switched from strong depression at postnatal day 12 (P12), to weaker depression and facilitation in mature cortex. However, presynaptic maturation was delayed by about two weeks at layer 4 (L4) to L2/3 excitatory synapses in visual cortex relative to barrel cortex. This developmental delay was pathway-specific: maturation of L2/3 to L2/3 synapses occurred over similar timescales in barrel and visual cortex. The developmental increase in the paired-pulse ratio (PPR) to values greater than unity was mirrored by a developmental decrease in presynaptic release probability. Therefore, L4 to L2/3 excitatory synapses had lower release probabilities and showed greater short-term facilitation in barrel cortex than in visual cortex at P28. Postsynaptic mechanisms could not account for the delayed maturation of STP in visual cortex. These findings indicate that synaptic development is delayed in the L4 to L2/3 pathway in visual cortex, and emphasise the need to take into account the changes in synaptic properties that occur during development when comparing plasticity mechanisms in different cortical areas.
mouse; barrel cortex; release probability; short-term plasticity; experience-dependent plasticity; postsynaptic