Short-term Synaptic Plasticity Research Articles

Disparities in Short-Term Depression Among Prefrontal Cortex Synapses Sustain Persistent Activity in a Balanced Network.

Persistent activity of cue-representing neurons in the prefrontal cortex (PFC) is regarded as a neural basis for working memory. The contribution of short-term synaptic plasticity (STP) at different types of synapses comprising the cortical network to persistent activity, however, remains unclear. Characterizing STP at synapses of the rat PFC layer 5 network, we found that PFC synapses exhibit distinct STP patterns according to presynaptic and postsynaptic identities. Excitatory postsynaptic currents (EPSCs) from corticopontine (Cpn) neurons were well sustained throughout continued activity, with stronger depression at synapses onto fast-spiking interneurons than those onto pyramidal cells. Inhibitory postsynaptic currents (IPSCs) were sustained at a weaker level compared with EPSC from Cpn synapses. Computational modeling of a balanced network incorporating empirically observed STP revealed that little depression at recurrent excitatory synapses, combined with stronger depression at other synapses, could provide the PFC with a unique synaptic mechanism for the generation and maintenance of persistent activity.

BDNF‐dependent phrenic motor facilitation: role of protein synthesis

Moderate acute intermittent hypoxia (mAIH) induces a form of respiratory motor plasticity known as phrenic long‐term facilitation (pLTF) — a persistent increase in inspiratory phrenic motor output that requires cervical spinal serotonin receptor activation and new synthesis of brain‐derived neurotrophic factor (BDNF). One fundamental difference between short‐term (minutes) and long‐term (days) synaptic plasticity is the reliance on transcription versus translation of genes required for protein synthesis. Although it is known that mAIH‐induced pLTF requires new synthesis of BDNF protein (Baker‐Herman et al. 2004), it is unknown if this form of plasticity also requires gene transcription. In turn, neurotrophins such as BDNF regulate synaptic transmission via rapid protein synthesis‐independent versus delayed protein synthesis‐dependent mechanisms. Although BDNF protein synthesis is necessary for mAIH‐induced pLTF, and cervical spinal application of exogenous BDNF is sufficient to elicit phrenic motor facilitation, it is unknown if phrenic motor facilitation requires new‐protein synthesis downstream from BDNF/TrkB signaling. Thus, we tested the hypotheses that: 1) mAIH‐induced pLTF requires transcriptional regulation of new protein synthesis, and 2) if translational regulation of new protein synthesis is necessary for BDNF‐induced phrenic motor facilitation. Experiments were performed on anesthetized, mechanically ventilated adult male Sprague Dawley rats. To inhibit spinal transcription, rats were pre‐treated with cervical spinal intrathecal injections of the transcription inhibitor triptolide, and then exposed to mAIH (3, 5‐min hypoxic episodes, PaO2 35–55 mmHg; 5 min intervals). To explore the requirement for new protein synthesis downstream from BDNF/TrkB signaling, a widely used translation inhibitor (emetine), was injected into the intrathecal space prior to BDNF injections. Intrathecal cervical spinal triptolide injections had no discernible effect on mAIH‐induced pLTF, demonstrating that pLTF does not require gene transcription. On the other hand, pre‐treatment with emetine blocked mAIH‐induced pLTF, confirming that pLTF requires new protein synthesis. Whereas cervical spinal BDNF injections induced phrenic motor facilitation similar to pLTF, its magnitude was unaffected by emetine pre‐treatment. Thus, BDNF/TrkB elicits phrenic motor facilitation via a mechanism that does not require additional protein synthesis. Collectively, our findings suggest that pLTF requires new synthesis of BDNF protein via translation‐dependent, transcription‐independent mechanisms, whereas additional new protein synthesis is not required downstream from BDNF/TrkB signaling. Thus, BDNF‐induced phrenic motor facilitation likely occurs exclusively via covalent modifications of existing proteins, presumably phosphorylation events mediated via BDNF/TrkB dependent activation of PKC‐q (Agosto‐Marlin & Mitchell, 2017).Support or Funding InformationNIH HL69064, HL111598 and the UF McKnight Brain InstituteThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Modulation of TARP γ8-Containing AMPA Receptors as a Novel Therapeutic Approach for Chronic Pain.

Nonselective glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists are efficacious in chronic pain but have significant tolerability issues, likely arising from the ubiquitous expression of AMPA receptors in the central nervous system (CNS). Recently, LY3130481 has been shown to selectively block AMPA receptors coassembled with the auxiliary protein, transmembrane AMPA receptor regulatory protein (TARP) γ8, which is highly expressed in the hippocampus but also in pain pathways, including anterior cingulate (ACC) and somatosensory cortices and the spinal cord, suggesting that selective blockade of γ8/AMPA receptors may suppress nociceptive signaling with fewer CNS side effects. The potency of LY3130481 on recombinant γ8-containing AMPA receptors was modulated by coexpression with other TARPs; γ2 subunits affected activity more than γ3 subunits. Consistent with these findings, LY3130481 had decreasing potency on receptors from rat hippocampal, cortical, spinal cord, and cerebellar neurons that was replicated in tissue from human brain. LY3130481 partially suppressed, whereas the nonselective AMPA antagonist GYKI53784 completely blocked, AMPA receptor-dependent excitatory postsynaptic potentials in ACC and spinal neurons in vitro. Similarly, LY3130481 attenuated short-term synaptic plasticity in spinal sensory neurons in vivo in response to stimulation of peripheral afferents. LY3130481 also significantly reduced nocifensive behaviors after intraplantar formalin that was correlated with occupancy of CNS γ8-containing AMPA receptors. In addition, LY3130481 dose-dependently attenuated established gait impairment after joint damage and tactile allodynia after spinal nerve ligation, all in the absence of motor side effects. Collectively, these data demonstrate that LY3130481 can suppress excitatory synaptic transmission and plasticity in pain pathways containing γ8/AMPA receptors and significantly reduce nocifensive behaviors, suggesting a novel, effective, and safer therapy for chronic pain conditions.

Overexpression of Calretinin Enhances Short-Term Synaptic Depression.

Analysis of the effects of various proteins on short-term synaptic plasticity is a difficult task, which may require the use of knockout animals. Here, we propose an alternative experimental approach for studying the roles of desired proteins in synaptic plasticity. We packed the Ca2+-binding protein calretinin and the fluorescent protein Venus into AAV and injected the concentrated viral suspension into the neocortex of newborn rats. The infected layer 2/3 pyramidal cells were identified in rat cortical slices using Venus fluorescence. Analysis of short-term synaptic plasticity using paired patch clamp recordings between layer 2/3 pyramidal cells (presynaptic cell) and fast-spiking (FS) interneurons (post-synaptic cell) showed that calretinin expression in the pyramidal cells did not change the failure rate in this synapse but did decrease synaptic delay. Analysis of the parameters of short-term synaptic plasticity showed that the amplitude of the first EPSP in the train was not affected by calretinin, however, calretinin strongly enhanced short-term depression. In addition, we found that the effect of calretinin depended on the presynaptic firing frequency: an increase in frequency resulted in enhancement of synaptic depression.

The Small and Dynamic Pre-primed Pool at the Release Site; A Useful Concept to Understand Release Probability and Short-Term Synaptic Plasticity?

Advanced imaging techniques have revealed that synapses contain nanomodules in which pre- and post-synaptic molecules are brought together to form an integrated subsynaptic component for vesicle release and transmitter reception. Based on data from an electrophysiological study of ours in which release from synapses containing a single nanomodule was induced by brief 50 Hz trains using minimal stimulation, and on data from such imaging studies, we present a possible modus operandi of such a nanomodule. We will describe the techniques and tools used to obtain and analyze the electrophysiological data from single CA3–CA1 hippocampal synapses from the neonatal rat brain. This analysis leads to the proposal that a nanomodule, despite containing a number of release locations, operates as a single release site, releasing at most a single vesicle at a time. In this nanomodule there appears to be two separate sets of release locations, one set that is responsible for release in response to the first few action potentials and another set that produces the release thereafter. The data also suggest that vesicles at the first set of release locations are primed by synaptic inactivity lasting seconds, this synaptic inactivity also resulting in a large heterogeneity in the values for vesicle release probability among the synapses. The number of vesicles being primed at this set of release locations prior to the arrival of an action potential is small (0–3) and varies from train to train. Following the first action potential, this heterogeneity in vesicle release probability largely vanishes in a release-independent manner, shaping a variation in paired-pulse plasticity among the synapses. After the first few action potentials release is produced from the second set of release locations, and is given by vesicles that have been recruited after the onset of synaptic activity. This release depends on the number of such release locations and the recruitment to such a location. The initial heterogeneity in vesicle release probability, its disappearance after a single action potential, and variation in the recruitment to the second set of release locations are instrumental in producing the heterogeneity in short-term synaptic plasticity among these synapses, and can be seen as means to create differential dynamics within a synapse population.

Low-Voltage Oxide-Based Synaptic Transistors for Spiking Humidity Detection

In order to obtain higher humidity sensitivity, shorter response/recover time, and lower energy consumption, we investigate the dynamic humidity sensing characteristics of indium–zinc-oxide (IZO)-based synaptic transistors with graphene oxide/chitosan composite electrolyte films as the gate dielectrics. Here, the short-term synaptic plasticity parameters, such as excitatory post-synaptic current, paired-pulse facilitation index, and high-pass filtering coefficient, were used for quantitative characterization of the relative humidity. The spiking humidity response time and energy consumption of such synaptic transistors are estimated to be 30 ms and 2.2 nJ, respectively. At the same time, a model based on the humidity-dependent proton gating and the adsorption of water molecules at the IZO channel surface is proposed.

Effect of adenosine on short-term synaptic plasticity in mouse piriform cortex invitro: adenosine acts as a high-pass filter.

We examined the effect of adenosine and of adenosine A1 receptor blockage on short‐term synaptic plasticity in slices of adult mouse anterior piriform cortex maintained in vitro in an in vivo‐like ACSF. Extracellular recording of postsynaptic responses was performed in layer 1a while repeated electrical stimulation (5‐pulse‐trains, frequency between 3.125 and 100 Hz) was applied to the lateral olfactory tract. Our stimulation protocol was aimed at covering the frequency range of oscillatory activities observed in the olfactory bulb in vivo. In control condition, postsynaptic response amplitude showed a large enhancement for stimulation frequencies in the beta and gamma frequency range. A phenomenological model of short‐term synaptic plasticity fitted to the data suggests that this frequency‐dependent enhancement can be explained by the interplay between a short‐term facilitation mechanism and two short‐term depression mechanisms, with fast and slow recovery time constants. In the presence of adenosine, response amplitude evoked by low‐frequency stimulation decreased in a dose‐dependent manner (IC50 = 70 μmol/L). Yet short‐term plasticity became more dominated by facilitation and less influenced by depression. Both changes compensated for the initial decrease in response amplitude in a way that depended on stimulation frequency: compensation was strongest at high frequency, up to restoring response amplitudes to values similar to those measured in control condition. The model suggested that the main effects of adenosine were to decrease neurotransmitter release probability and to attenuate short‐term depression mechanisms. Overall, these results suggest that adenosine does not merely inhibit neuronal activity but acts in a more subtle, frequency‐dependent manner.

Dynamic Control of Vesicle Priming in Synaptic Short-Term Plasticity

Dynamic Control of Vesicle Priming in Synaptic Short-Term Plasticity

Si-Based FET-Type Synaptic Device With Short-Term and Long-Term Plasticity Using High-<inline-formula> <tex-math notation="LaTeX">$\kappa$ </tex-math> </inline-formula> Gate-Stack

In this paper, we investigate the characteristics of short-term and long-term synaptic plasticity in a Si-based field-effect transistor-type memory device. An Al2O3/HfO2/Si3N4 gate dielectric stack is used to realize short-term and long-term plasticity (STP/LTP). Si3N4 and HfO2 layers are designed to implement short-term and long-term memory, respectively. The mechanism of STP and LTP operation has been figured out by analyzing the device response to the potentiation and depression pulses. To investigate the STP operation, paired-pulse facilitation measurement is performed. The retention characteristic is also studied to validate the LTP property of the device. By investigating a device with an Al2O3/Si3N4 stack as a control device, it is shown that the HfO2 layer contributes to LTP in device with Al2O3/HfO2/Si3N4 stack. Thus, it is confirmed that STP and LTP operations can be implemented simultaneously in devices with an Al2O3/HfO2/Si3N4 stack.

Presenting a Neuroid model of wind-up based on dynamic synapse

The treatment of chronic pain depends mainly on our understanding of the mechanisms such as central sensitization which is involved in it. Wind-up of spinal cord is one of the most important phenomena in the study of central sensitization which has received considerable attention in recent years. Wind-up is a form of short-term synaptic plasticity (STP) that can lead to central sensitivity. Although several models have been proposed for wind-up, none of them are based on the experimental evidence. In this study, a new network model is introduced according to the gate control theory of pain. Neuroids are used as neuron models in which their parameters are captured from available experimental data. Adjusting the weights of the network is based on the short-term synaptic plasticity. The results of the time and frequency domain show that the model can well simulate wind-up behavior. This model can be used for analyzing, predicting and controlling chronic pain in the future.

Okadaic acid attenuates short-term and long-term synaptic plasticity of hippocampal dentate gyrus neurons in rats.

Protein phosphorylation states have a pivotal role in regulation of synaptic plasticity and long-term modulation of synaptic transmission. Serine/threonine protein phosphatase 1 (PP1) and 2A (PP2A) have a critical effect on various regulatory mechanisms involved in synaptic plasticity, learning and memory. Okadaic acid (OKA), a potent inhibitor of PP1 and PP2A, reportedly leads to cognitive decline and Alzheimer's disease (AD)-like pathology. The aim of this study was to examine the effect of OKA on electrophysiological characteristics of hippocampal dentate gyrus (DG) neurons in vivo. Male Wistar rats were divided into two control and OKA groups. OKA was injected intracerebroventricularly (i.c.v.) into lateral ventricles and after two weeks the long-term potentiation (LTP) and paired-pulse responses recorded from hippocampal perforant path-DG synapses in order to assess short-term and long-term synaptic plasticity. Results of this study revealed that OKA-induced inhibition of PP1 and PP2A activity drastically attenuates the field excitatory postsynaptic potential (fEPSP) slope and population spike (PS) amplitude following paired pulse and high frequency stimulation (HFS) of hippocampal DG neurons indicating pre- and post-synaptic involvement in electrical activity of these neurons. Administration of OKA impaired the short-term and long-term spatial memories conducted by Y-maze and passive avoidance tests, respectively. OKA-induced attenuation in electrophysiological activity and consequent memory deficits also provide a beneficial tool for studying neurodegenerative disorders such as AD.

A mathematical model of synaptotagmin 7 revealing functional importance of short-term synaptic plasticity.

Synaptotagmin 7 (Syt7), a presynaptic calcium sensor, has a significant role in the facilitation in short-term synaptic plasticity: Syt7 knock out mice show a significant reduction in the facilitation. The functional importance of short-term synaptic plasticity such as facilitation is not well understood. In this study, we attempt to investigate the potential functional relationship between the short-term synaptic plasticity and postsynaptic response by developing a mathematical model that captures the responses of both wild-type and Syt7 knock-out mice. We then studied the model behaviours of wild-type and Syt7 knock-out mice in response to multiple input action potentials. These behaviors could establish functional importance of short-term plasticity in regulating the postsynaptic response and related synaptic properties. In agreement with previous modeling studies, we show that release sites are governed by non-uniform release probabilities of neurotransmitters. The structure of non-uniform release of neurotransmitters makes short-term synaptic plasticity to act as a high-pass filter. We also propose that Syt7 may be a modulator for the long-term changes of postsynaptic response that helps to train the target frequency of the filter. We have developed a mathematical model of short-term plasticity which explains the experimental data.

Changes in Functional Properties of Rat Hippocampal Neurons Following Pentylenetetrazole-induced Status Epilepticus

Pathophysiological remodeling processes following status epilepticus (SE) play a critical role in the pathophysiology of epilepsy but have not yet been not fully investigated. In the present study, we examined changes in intrinsic properties of pyramidal neurons, basal excitatory synaptic transmission, and short-term synaptic plasticity in hippocampal slices of rats after SE. Seizures were induced in 3-week-old rats by an intraperitoneal pentylenetetrazole (PTZ) injection. Only animals with generalized seizures lasting more than 30 min were included in the experiments. We found that CA1 pyramidal neurons became more excitable and started firing at a lower excitatory input due to a significant increase in input resistance. However, basal excitatory synaptic transmission was reduced in CA3-CA1 synapses, thus preventing the propagation of excitation through neural networks. A significant increase in paired-pulse facilitation 1 d after SE pointed to a decrease in the probability of glutamate release. Increased intrinsic excitability of neurons and decreased synaptic transmission differentially affected the excitability of a neural network. In terms of changes in seizure susceptibility after SE, we observed a significant increase in the maximal electroshock threshold 1 day after SE, suggesting a decrease in seizure susceptibility. However, after 1 week, there was no difference in seizure susceptibility between control and post-SE rats. The effects of SE on functional properties of hippocampal neurons were transient in the PTZ model, and most of them had recovered 1 week after SE. However, some minor alterations, such as smaller amplitude field potentials, were observed 1 month after SE.

Dynamic Communications Between GABAA Switch, Local Connectivity, and Synapses During Cortical Development: A Computational Study.

Several factors regulate cortical development, such as changes in local connectivity and the influences of dynamical synapses. In this study, we simulated various factors affecting the regulation of neural network activity during cortical development. Previous studies have shown that during early cortical development, the reversal potential of GABAA shifts from depolarizing to hyperpolarizing. Here we provide the first integrative computational model to simulate the combined effects of these factors in a unified framework (building on our prior work: Khalil et al., 2017a,b). In the current study, we extend our model to monitor firing activity in response to the excitatory action of GABAA. Precisely, we created a Spiking Neural Network model that included certain biophysical parameters for lateral connectivity (distance between adjacent neurons) and nearby local connectivity (complex connections involving those between neuronal groups). We simulated different network scenarios (for immature and mature conditions) based on these biophysical parameters. Then, we implemented two forms of Short-term synaptic plasticity (depression and facilitation). Each form has two distinct kinds according to its synaptic time constant value. Finally, in both sets of networks, we compared firing rate activity responses before and after simulating dynamical synapses. Based on simulation results, we found that the modulation effect of dynamical synapses for evaluating and shaping the firing activity of the neural network is strongly dependent on the physiological state of GABAA. Moreover, the STP mechanism acts differently in every network scenario, mirroring the crucial modulating roles of these critical parameters during cortical development. Clinical implications for pathological alterations of GABAergic signaling in neurological and psychiatric disorders are discussed.

Impaired anandamide/palmitoylethanolamide signaling in hippocampal glutamatergic neurons alters synaptic plasticity, learning, and emotional responses

Endocannabinoid signaling via anandamide (AEA) is implicated in a variety of neuronal functions and considered a promising therapeutic target for numerous emotion-related disorders. The major AEA degrading enzyme is fatty acid amide hydrolase (FAAH). Genetic deletion and pharmacological inhibition of FAAH reduce anxiety and improve emotional responses and memory in rodents and humans. Complementarily, the mechanisms and impact of decreased AEA signaling remain to be delineated in detail. In the present study, using the Cre/loxP system combined with an adeno-associated virus (AAV)-mediated delivery system, FAAH was selectively overexpressed in hippocampal CA1-CA3 glutamatergic neurons of adult mice. This approach led to specific FAAH overexpression at the postsynaptic site of CA1-CA3 neurons, to increased FAAH enzymatic activity, and, in consequence, to decreased hippocampal levels of AEA and palmitoylethanolamide (PEA), but the levels of the second major endocannabinoid 2-arachidonoyl glycerol (2-AG) and of oleoylethanolamide (OEA) were unchanged. Electrophysiological recordings revealed an enhancement of both excitatory and inhibitory synaptic activity and of long-term potentiation (LTP). In contrast, excitatory and inhibitory long-term depression (LTD) and short-term synaptic plasticity, apparent as depolarization-induced suppression of excitation (DSE) and inhibition (DSI), remained unaltered. These changes in hippocampal synaptic activity were associated with an increase in anxiety-like behavior, and a deficit in object recognition memory and in extinction of aversive memory. This study indicates that AEA is not involved in hippocampal short-term plasticity, or eLTD and iLTD, but modulates glutamatergic transmission most likely via presynaptic sites, and that disturbances in this process impair learning and emotional responses.

Intermediate-term memory in Aplysia involves neurotrophin signaling, transcription, and DNA methylation

Long-term but not short-term memory and synaptic plasticity in many brain areas require neurotrophin signaling, transcription, and epigenetic mechanisms including DNA methylation. However, it has been difficult to relate these cellular mechanisms directly to behavior because of the immense complexity of the mammalian brain. To address that problem, we and others have examined numerically simpler systems such as the hermaphroditic marine mollusk Aplysia californica. As a further simplification, we have used a semi-intact preparation of the Aplysia siphon withdrawal reflex in which it is possible to relate cellular plasticity directly to behavioral learning. We find that inhibitors of neurotrophin signaling, transcription, and DNA methylation block sensitization and classical conditioning beginning ∼1 h after the start of training, which is in the time range of an intermediate-term stage of plasticity that combines elements of short- and long-term plasticity and may form a bridge between them. Injection of decitabine (an inhibitor of DNA methylation that may have other actions in these experiments) into an LE sensory neuron blocks the neural correlates of conditioning in the same time range. In addition, we found that both DNA and RNA methylation in the abdominal ganglion are correlated with learning in the same preparations. These results begin to suggest the functions and integration of these different molecular mechanisms during behavioral learning.

Molecular mechanisms that stabilize short term synaptic plasticity during presynaptic homeostatic plasticity.

Presynaptic homeostatic plasticity (PHP) compensates for impaired postsynaptic neurotransmitter receptor function through a rapid, persistent adjustment of neurotransmitter release, an effect that can exceed 200%. An unexplained property of PHP is the preservation of short-term plasticity (STP), thereby stabilizing activity-dependent synaptic information transfer. We demonstrate that the dramatic potentiation of presynaptic release during PHP is achieved while simultaneously maintaining a constant ratio of primed to super-primed synaptic vesicles, thereby preserving STP. Mechanistically, genetic, biochemical and electrophysiological evidence argue that a constant ratio of primed to super-primed synaptic vesicles is achieved by the concerted action of three proteins: Unc18, Syntaxin1A and RIM. Our data support a model based on the regulated availability of Unc18 at the presynaptic active zone, a process that is restrained by Syntaxin1A and facilitated by RIM. As such, regulated vesicle priming/super-priming enables PHP to stabilize both synaptic gain and the activity-dependent transfer of information at a synapse.

Molecular Mechanisms of Short-Term Plasticity: Role of Synapsin Phosphorylation in Augmentation and Potentiation of Spontaneous Glutamate Release.

We used genetic and pharmacological approaches to identify the signaling pathways involved in augmentation and potentiation, two forms of activity dependent, short-term synaptic plasticity that enhance neurotransmitter release. Trains of presynaptic action potentials produced a robust increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs). Following the end of the stimulus, mEPSC frequency followed a bi-exponential decay back to basal levels. The time constants of decay identified these two exponential components as the decay of augmentation and potentiation, respectively. Augmentation increased mEPSC frequency by 9.3-fold, while potentiation increased mEPSC frequency by 2.4-fold. In synapsin triple-knockout (TKO) neurons, augmentation was reduced by 83% and potentiation was reduced by 74%, suggesting that synapsins are key signaling elements in both forms of plasticity. To examine the synapsin isoforms involved, we expressed individual synapsin isoforms in TKO neurons. While synapsin IIIa rescued both augmentation and potentiation, none of the other synapsin isoforms produced statistically significant amounts of rescue. To determine the involvement of protein kinases in these two forms of short-term plasticity, we examined the effects of inhibitors of protein kinases A (PKA) and C (PKC). While inhibition of PKC had little effect, PKA inhibition reduced augmentation by 76% and potentiation by 60%. Further, elevation of intracellular cAMP concentration, by either forskolin or IBMX, greatly increased mEPSC frequency and occluded the amount of augmentation and potentiation evoked by electrical stimulation. Finally, mutating a PKA phosphorylation site to non-phosphorylatable alanine largely abolished the ability of synapsin IIIa to rescue both augmentation and potentiation. Together, these results indicate that PKA activation is required for both augmentation and potentiation of spontaneous neurotransmitter release and that PKA-mediated phosphorylation of synapsin IIIa underlies both forms of presynaptic short-term plasticity.

Anterograde and retrograde signaling by an Aplysia neurotrophin forms a transsynaptic functional unit

Whereas short-term synaptic plasticity is often either pre- or postsynaptic, intermediate- and long-term plasticity generally require coordinated pre- and postsynaptic mechanisms. Thus, the transition from presynaptic short-term facilitation (STF) to intermediate-term facilitation (ITF) induced by 5HT at Aplysia sensory-to-motor neuron synapses requires the recruitment of postsynaptic mechanisms and activation of protein synthesis in both neurons. In the companion paper to this report, we found that presynaptic autocrine signaling by an Aplysia neurotrophin (ApNT) forms a positive feedback loop that drives the synapses from STF to ITF. Here we report that ApNT also acts through both anterograde and retrograde signaling to form a transsynaptic positive feedback loop that orchestrates cellular functions in both the presynaptic and postsynaptic neurons during the induction of ITF. These two feedback loops activate protein synthesis in each synaptic compartment, which in both cases depends on signaling from the other synaptic compartment. These results suggest that the pre- and postsynaptic compartments act as one functional unit during the consolidation of learning-related facilitation induced by 5HT.

Short-Term Plasticity at Olfactory Cortex to Granule Cell Synapses Requires CaV2.1 Activation.

Output projections of the olfactory bulb (OB) to the olfactory cortex (OCX) and reciprocal feedback projections from OCX provide rapid regulation of OB circuit dynamics and odor processing. Short-term synaptic plasticity (STP), a feature of many synaptic connections in the brain, can modulate the strength of feedback based on preceding network activity. We used light-gated cation channel channelrhodopsin-2 (ChR2) to investigate plasticity of excitatory synaptic currents (EPSCs) evoked at the OCX to granule cell (GC) synapse in the OB. Selective activation of OCX glutamatergic axons/terminals in OB generates strong, frequency-dependent STP in GCs. This plasticity was critically dependent on activation of CaV2.1 channels. As acetylcholine (ACh) modulates CaV2.1 channels in other brain regions and as cholinergic projections from the basal forebrain heavily target the GC layer (GCL) in OB, we investigated whether ACh modulates STP at the OCX→GC synapse. ACh decreases OCX→GC evoked EPSCs, it had no effect on STP. Thus, ACh impact on cortical feedback is independent of CaV2.1-mediated STP. Modulation of OCX feedback to the bulb by modulatory transmitters, such as ACh, or by frequency-dependent STP could regulate the precise balance of excitation and inhibition of GCs. As GCs are a major inhibitory source for OB output neurons, plasticity at the cortical feedback synapse can differentially impact OB output to higher-order networks in situations where ACh inputs are activated or by active sniff sampling of odors.