Efficacy Of Synaptic Transmission Research Articles

Nanodomain coupling between Ca2+ channels and sensors of exocytosis at fast mammalian synapses

The physical distance between presynaptic Ca(2+) channels and the Ca(2+) sensors that trigger exocytosis of neurotransmitter-containing vesicles is a key determinant of the signalling properties of synapses in the nervous system. Recent functional analysis indicates that in some fast central synapses, transmitter release is triggered by a small number of Ca(2+) channels that are coupled to Ca(2+) sensors at the nanometre scale. Molecular analysis suggests that this tight coupling is generated by protein-protein interactions involving Ca(2+) channels, Ca(2+) sensors and various other synaptic proteins. Nanodomain coupling has several functional advantages, as it increases the efficacy, speed and energy efficiency of synaptic transmission.

Neuregulin/ErbB regulate neuromuscular junction development by phosphorylation of α-dystrobrevin

Neuregulin (NRG)/ErbB signaling is involved in numerous developmental processes in the nervous system, including synapse formation and function in the central nervous system. Although intensively investigated, its role at the neuromuscular synapse has remained elusive. Here, we demonstrate that loss of neuromuscular NRG/ErbB signaling destabilized anchoring of acetylcholine receptors (AChRs) in the postsynaptic muscle membrane and that this effect was caused by dephosphorylation of α-dystrobrevin1, a component of the postsynaptic scaffold. Specifically, in mice in which NRG signaling to muscle was genetically or pharmacologically abolished, postsynaptic AChRs moved rapidly from the synaptic to the perisynaptic membrane, and the subsynaptic scaffold that anchors the AChRs was impaired. These defects combined compromised synaptic transmission. We further show that blockade of NRG/ErbB signaling abolished tyrosine phosphorylation of α-dystrobrevin1, which reduced the stability of receptors in agrin-induced AChR clusters in cultured myotubes. Our data indicate that NRG/ErbB signaling maintains high efficacy of synaptic transmission by stabilizing the postsynaptic apparatus via phosphorylation of α-dystrobrevin1.

Dual actions of brain-derived neurotrophic factor on GABAergic transmission in cerebellar Purkinje neurons

The ability to regulate inhibitory synapses is a critical feature of the nervous system and a growing body of evidence indicates that brain-derived neurotrophic factor (BDNF) acutely modulates the efficacy of GABA synaptic transmission. Although the neuronal potassium-chloride cotransporter 2 (KCC2) has been implied in this BDNF-induced ionic plasticity, the reports about actions of BDNF on GABA signaling remain conflicting. Here we show dual effects of BDNF on GABAergic synaptic transmission in Purkinje neurons in rat cerebellar slices. BDNF decreased the amplitude of evoked outward IPSCs postsynaptically. It induced a depolarizing shift in the reversal potential (EIPSC), which reduced the driving force for outward IPSCs. However, in the absence of KCC2 activity, BDNF directly potentiated rather than inhibited GABAA receptor, which was reflected by an increase in the amplitude of outward IPSCs. This action of BDNF coincided with its effect in increasing the amplitude of inward IPSCs. Furthermore, an interaction between GABAA receptor and KCC2 was revealed by co-immunoprecipitation. The effects of BDNF on both GABAA receptor and KCC2 were dependent on TrkB and also activation of cyclin-dependent kinase 5 (Cdk5). However, only the effect of BDNF on KCC2 activity was dependent on a rise of intracellular calcium. Taken together, these data highlight distinct actions of BDNF on KCC2 and GABAA receptor in the regulation of GABAergic synaptic transmission.

Crashpilot Underachieves due to Acetylation at the Nerve Terminal

Protein acetylation is mostly known for its role in chromatin remodeling. In this issue, Miśkiewicz and colleagues reveal a novel function of acetylation at the nerve terminal, where it regulates T bars and the number of associated synaptic vesicles to ultimately control the efficacy of synaptic transmission.

Changes in synaptic efficacy of dentate granule cells during operant behavior in rats

It is widely accepted that long-term potentiation (LTP) is one of the fundamental physiological mechanisms underlying memory function based on its response properties and behavior of the induced sites. Many experimental approaches have been used to investigate whether the mechanisms underlying LTP are activated during learning and whether these mechanisms underlie the formation of certain types of memory. However, relatively few studies have reported the time course of changes in the efficacy of synaptic transmission in the learning process. We simultaneously monitored changes in slope of field EPSPs (fEPSP slope) and the amplitude of population spikes (pop. spike) in perforant path-evoked potentials in the dentate gyrus over the course of an appetitively motivated operant paradigm in freely moving rats. We found that the fEPSP slope recorded from the granule cell layer was potentiated about 7%, the fEPSP slope recorded from the molecular layer was depressed about 20%, and the amplitude of pop. spike recorded from the granule cell layer was significantly depressed about 40% after the trial in which rats began to press the lever frequently. These results suggested that the granule cells in the dentate gyrus received excitatory inputs in the somatic region and inhibitory inputs in the dendritic region, and that outputs from the granule cells were significantly reduced in the process of acquisition of the operant behavioral task. We observed no LTP in this study although our rats were capable of having LTP induced by a high-frequency stimulus. The depression of fEPSP slope induced without any artificial stimulation in this study is thought to be another neural mechanism underlying learning and memory. The origins of excitatory and inhibitory inputs are unknown at the moment.

The reduction of growth hormone enhances the efficacy of basal synaptic transmission and LTP in the rat hippocampal CA1 region

The reduction of growth hormone enhances the efficacy of basal synaptic transmission and LTP in the rat hippocampal CA1 region

Dynamic Neural Control of Insect Muscle Metabolism Related to Motor Behavior

Skeletal muscle innervation differs between vertebrates and insects. Insect muscle fibers exhibit graded electrical potentials and are innervated by excitatory, inhibitory, and also neuromodulatory motoneurons. The latter form a unique class of unpaired neurons with bilaterally symmetrical axons that release octopamine to alter the efficacy of synaptic transmission and regulate muscle energy metabolism by activating glycolysis. Octopaminergic neurons that innervate muscles with a high energy demand, for example, flight muscles that move the wings of a locust up and down, are active during rest but are inhibited during flight and its preparatory phase, a jump. Therefore, it is argued that these neurons are involved in providing locusts with the necessary fuel at takeoff, but then may aid the switch to lipid oxidation during flight. In general, the octopaminergic system may switch the whole organism from a tonic to a dynamic state.

Cellular and network mechanisms of cholinergically-induced transition between gamma and sharp wave – ripple network states in the hippocampus

In different behavioral states cortical networks show distinct dynamics, which may implement distinct computations. Switching between network states may be brought about by subcortical modulatory inputs, which affect both single cell and synaptic properties, but the actual mechanisms are currently unknown. Hippocampal activity in awake rodents is characterized by the behavior-associated alteration of theta-modulated gamma activity, associated with exploration, and sharp wave – ripple (SPW-R) activity, associated with alert stillness. We take advantage of the recent development of an in vitro slice preparation where these activity patterns either emerge spontaneously or can be induced by the application of neuromodulatory substances, to investigate, via the combination of electrophysiological and modeling tools, the link between changes in neuronal characteristics and the resulting switches in emergent network behavior. By improving the preparation and maintenance conditions of in vitro slices, we managed to record activity patterns identical to in vivo described SPW-Rs and gamma activity from the CA3 area. Under baseline conditions the slices spontaneously generated SPW-Rs with characteristics similar to those observed in vivo. Mimicking the increased cholinergic tone during the theta-gamma state in vivo by the application of the cholinergic agonist carbachol (3-5uM, CCH), the SPW-R activity can be quickly (1-2 minutes) and reversibly converted into gamma activity. In the SPW-R state, activity levels were generally low, but activity in the network could transiently build up to an intensely activated, highly synchronous state. In the gamma state, activity levels were sustained at a high level, and synchrony increased rhythmically in each cycle, but never reached levels seen during SPW-Rs. In order to explain these qualitative changes in network behavior, we hypothesize that two network parameters change concurrently during the SPW-R to gamma transition, caused by the increasing cholinergic tone: 1) a cellular parameter: the excitability of principal neurons increases (this is responsible for the increased frequency of network activation), while 2) a network parameter: the strength of synaptic connections decreases (this limits the spread of activity in the network before inhibition terminates it). We measured the effects of CCH on the excitability of single pyramidal cells and perisomatic interneurons, and determined how CCH changes the efficacy of transmission between these cell types in CA3. We confirmed that CCH increased cellular excitability (mainly in pyramidal cells), and found that CCH substantially decreased the efficacy of synaptic transmission in all connections examined, but it especially strongly attenuated excitatory synaptic transmission. Finally, we developed a large-scale model of the CA3 area of a hippocampal slice, consisting of integrate-and-fire models of pyramidal cells and interneurons. Single cell and synaptic properties were determined experimentally in both network states. Our model confirmed that the measured cellular and synaptic changes are sufficient to explain the observed switching between the two types of network dynamics, and also suggested possible mechanisms for the initiation and termination of sharp wave events. it suggested that the initiation of sharp waves relies on random fluctuations of population activity, while the termination of sharp waves probably requires some novel form of slow negative feedback.

The antidepressant fluoxetine but not citalopram suppresses synapse formation and synaptic transmission between Lymnaea neurons by perturbing presynaptic and postsynaptic machinery

Depression is a debilitating mental disorder, and selective serotonin reuptake inhibitors (SSRIs) constitute the first-line antidepressant treatment choice for the clinical management of this illness; however, the mechanisms underlying their therapeutic actions and side effects remain poorly understood. Here, we compared the effects of two SSRIs, fluoxetine and citalopram, on synaptic connectivity and the efficacy of cholinergic synaptic transmission between identified presynaptic and postsynaptic neurons from the mollusc Lymnaea. The in vitro paired cells were exposed to clinically relevant concentrations of the two SSRIs under chronic and acute experimental conditions, and the incidence of synapse formation and the efficacy of synaptic transmission were tested electrophysiologically and with fluorescent Ca(2+) imaging. We demonstrate that chronic exposure to fluoxetine, but not to citalopram, inhibits synapse formation and reduces synaptic strength, and that these effects are reversible following prolonged drug washout. At the structural level, we demonstrate that fluoxetine, but not citalopram, prevents the expression and localization of the presynaptic protein synaptophysin. Acute exposure to fluoxetine substantially reduced synaptic transmission and synaptic plasticity (post-tetanic potentiation) in established synapses, whereas citalopram reduced synaptic transmission, but not short-term synaptic plasticity. We further demonstrate that fluoxetine, but not citalopram, directly inhibits voltage-gated Ca(2+) currents in the presynaptic neuron, as well as postsynaptic responsiveness to exogenously applied neurotransmitter. This study provides the first direct evidence that fluoxetine and citalopram exert characteristic, non-specific side effects that are unrelated to their function as SSRIs, and that fluoxetine is more detrimental to synaptic physiology and structure than citalopram.

Follistatin-like 1 Suppresses Sensory Afferent Transmission by Activating Na+,K+-ATPase

Excitatory synaptic transmission is modulated by inhibitory neurotransmitters and neuromodulators. We found that the synaptic transmission of somatic sensory afferents can be rapidly regulated by a presynaptically secreted protein, follistatin-like 1 (FSTL1), which serves as a direct activator of Na(+),K(+)-ATPase (NKA). The FSTL1 protein is highly expressed in small-diameter neurons of the dorsal root ganglion (DRG). It is transported to axon terminals via small translucent vesicles and secreted in both spontaneous and depolarization-induced manners. Biochemical assays showed that FSTL1 binds to the α1 subunit of NKA and elevates NKA activity. Extracellular FSTL1 induced membrane hyperpolarization in cultured cells and inhibited afferent synaptic transmission in spinal cord slices by activating NKA. Genetic deletion of FSTL1 in small DRG neurons of mice resulted in enhanced afferent synaptic transmission and sensory hypersensitivity, which could be reduced by intrathecally applied FSTL1 protein. Thus, FSTL1-dependent activation of NKA regulates the threshold of somatic sensation.

Dopamine induces a GluN2A-dependent form of long-term depression of NMDA synaptic responses in the nucleus accumbens

Natural rewards and addictive drugs are believed to exert their reinforcing actions by influencing synaptic plasticity in reward-related brain regions such as the nucleus accumbens (NAc). Long-lasting changes in the efficacy of excitatory synaptic transmission in the NAc are critically dependent on efficient interactions between the dopaminergic and the glutamatergic neurotransmitter systems. Potential targets to the actions of dopamine and of addictive drugs include the GluN2 subunits that compose the N-Methyl- d-Aspartate (NMDA) type of glutamate receptors. However, the ability of dopamine to induce synaptic plasticity by modulating specific subunits of the NMDA receptor has not been examined. The present study shows that in the mouse NAc, dopamine produces a long-lasting depression of NMDA responses which occludes long-term depression (LTD) induced by high frequency stimulation (HFS) of glutamatergic fibers. LTD induced by dopamine or by HFS does not involve a change in the subunit composition of NMDA receptors. Although GluN2B contributes to synaptic responses in the NAc and is affected by dopamine, this subunit might not be a direct target to the actions of dopamine. The results, however, identify a critical role for GluN2A in dopamine-induced and HFS-induced synaptic plasticity. This study suggests a possible mechanism of action for dopamine in the regulation of reward-related behaviors.

The involvement of potassium ion channels in memory

Hippocampal long-term potentiation (LTP), an increase in the efficacy of synaptic transmission, has been considered a powerful candidate for the physiological basis of memory. Although hippocampal LTP has been induced by high frequency electrical stimulation of the presynaptic fiber in most studies, it has been reported that pharmacological blockade of potassium ion channels also induces synaptic plasticity. Furthermore, several studies have recently used a newly developed selective blocker and opener to demonstrate that potassium ion channels play an important role in memory and learning. This article reviews studies that have shown the possible involvement of potassium ion channels in memory function and hippocampal synaptic plasticity.

Long-Term Potentiation at CA3–CA1 Hippocampal Synapses with Special Emphasis on Aging, Disease, and Stress

Synaptic plasticity in the mammalian central nervous system has been the subject of intense investigation for the past four decades. Long-term potentiation (LTP), a major reflection of synaptic plasticity, is an activity-driven long-lasting increase in the efficacy of excitatory synaptic transmission following the delivery of a brief, high-frequency train of electrical stimulation. LTP is regarded as a principal candidate for the cellular mechanisms involved in learning and offers an attractive hypothesis of how memories are constructed. There are a number of exceptional full-length reviews published on LTP; the current review intends to present an overview of the research findings regarding hippocampal LTP with special emphasis on aging, diseases, and psychological insults.

Private Placements: A Theoretical Assessment of SECNo-Action Letters

<h3>ABSTRACT</h3> Information processing by the nervous system depends on the release of neurotransmitter from synaptic vesicles (SVs) at the presynaptic active zone. Molecular components of the cytomatrix at the active zone (CAZ) regulate the final stages of the SV cycle preceding exocytosis and thereby shape the efficacy and plasticity of synaptic transmission. Part of this regulation is reflected by a physical association of SVs with filamentous CAZ structures. However, our understanding of the protein interactions underlying SV tethering by the CAZ is far from complete. The very C-terminal region of Bruchpilot (Brp), a key component of the <i>Drosophila</i> CAZ, participates in SV tethering. Yet so far, no vesicular or cytoplasmic molecules have been reported to engage in an interaction with Brp’s C-terminus. Here, we carried out an in vivo screen for molecules that link the Brp C-terminus to SVs. This strategy identified the conserved SNARE (soluble <i>N</i>-ethylmaleimide-sensitive factor (NSF) attachment protein receptor) regulator Complexin (Cpx) as a vesicular interaction partner of Brp. We show that Brp and Cpx interact genetically and functionally. Interfering with Cpx targeting to SVs mirrored distinctive features of a C-terminal Brp truncation: impaired SV recruitment to the CAZ and enhanced short-term synaptic depression. Extending the study beyond <i>Drosophila</i> synapses, we interrogated active zones of mouse rod bipolar cells. Here, too, we collected evidence for an evolutionarily conserved role of Cpx upstream of SNARE complex assembly where it participates in SV tethering to the CAZ.

Long-Term Depression at Parallel Fiber to Golgi Cell Synapses

Golgi cells (GoCs) are the primary inhibitory interneurons of the granular layer of the cerebellum. Their inhibition of granule cells is central to operate the relay of excitatory inputs to the cerebellar cortex. Parallel fibers (PFs) establish synapses to the GoCs in the molecular layer; these synapses contain AMPA, N-methyl-D-aspartate (NMDA), and mostly group II metabotropic glutamate receptors. Long-term changes in the efficacy of synaptic transmission at the PF-GoC synapse have not been described previously. We used whole cell patch-clamp recordings of GoCs in acute rat cerebellar slices to study synaptic plasticity. We report that high-frequency burst stimulation of PFs, using a current-clamp or voltage-clamp induction protocol, gave rise to long-term depression (LTD) at the PF-GoC synapse. This form of LTD was not associated with persistent changes of paired-pulse ratio, suggesting a postsynaptic origin. Furthermore, LTD induction was not dependent on activation of NMDA receptors. PF-GoC LTD does require activation of specifically group II metabotropic glutamate receptors and of protein kinase A.

Dynamics of the Rapsyn Scaffolding Protein at the Neuromuscular Junction of Live Mice

The efficacy of synaptic transmission depends on the maintenance of a high density of neurotransmitter receptors and their associated scaffold proteins in the postsynaptic membrane. While the dynamics of receptors has been extensively studied, the dynamics of the intracellular scaffold proteins that make up the postsynaptic density are largely unknown in vivo. Here, we focused on the dynamics of rapsyn, a protein required for the clustering and maintenance of acetylcholine receptor (AChR) density at postsynaptic sites. Using time-lapse imaging, we demonstrated that rapsyn is remarkably dynamic compared to AChRs at functional synapses, turning over 4-6 times more rapidly than AChRs. In addition we found that the rapid turnover of rapsyn is insensitive to alterations in synaptic activity, whereas AChR turnover is profoundly affected, illustrating that rapsyn and receptor dynamics are controlled by distinct mechanisms. These data indicate that individual postsynaptic components are in permanent exchange despite the overall stability of synaptic structure, which may play a role in synaptic plasticity.

Late expression of brain-derived neurotrophic factor in the amygdala is required for persistence of fear memory

In many instances, increase in neuronal activity can induce biphasic secretion of a modulator. The initial release of the modulator triggers the induction of synaptic plasticity, whereas the second-phase release reinforces the efficacy of synaptic transmission and growth of dendrites and axons. In this study, we showed that fear conditioning not only induced the first but also a second peak of brain-derived neurotrophic factor (BDNF) expression. Fluorescent immunohistostaining confirmed that BDNF expression increased at 1 and 12 h after conditioning and returned to baseline at 30 h after conditioning. Mature BDNF expression increased in a similar manner. TrkB-IgG or K252a infusion before training impaired fear memory on days 1 and 7 after training. In contrast, TrkB-IgG or K252a infusion 9 h after fear conditioning did not affect memory retention on day 1 after training but impaired fear memory on day 7 after training. Fear conditioning significantly enhanced Zif268 expression in the amygdala at 12 h after training; this enhanced expression was completely inhibited by TrkB-IgG infusion 9 h after training. The level of growth-associated protein 43 (GAP-43), a marker of newly formed synapses, in the amygdala increased 7 days after fear conditioning. Moreover, conditioned rats had higher AMPA/NMDA ratio than unpaired rats. These results suggest that consolidated memory could be continuously modulated by previous molecular changes produced during memory acquisition.

Activity-dependent recruitment of AMPA receptors to the postsynaptic compartment by facilitated diffusion in the plasma membrane

The brain operates by continually transmitting and processing vast amounts of data through complex networks of neurones. This information is transmitted via the release and detection of neurotransmitters at synapses. In the mammalian brain the predominant excitatory neurotransmitter is glutamate that acts at several types of glutamate receptors located at, or near, the postsynaptic density on specialised dendritic protrusions called spines. The ability of neurones to modulate the efficacy of synaptic transmission in response to previous activity at that synapse, termed synaptic plasticity, is fundamental to cognitive processes such as memory and learning. AMPA receptors (AMPARs) are a subclass of glutamate receptor, which mediate nearly all fast excitatory neurotransmission. Synaptic plasticity largely depends on the activity-dependent trafficking of AMPARs into and out of spines. Thus, a major challenge in neuroscience is to better understand how neurotransmitter receptors get to the right synapse at the right time and how their numbers within spines and at the postsynaptic density are maintained and regulated. We recently reported results that offer a mechanistic explanation of how AMPARs can be recruited to spines by synaptic activity. In this addendum we address technical aspects of this work and further discuss the context and implications of our data.

Disinhibition Mediates a Form of Hippocampal Long-Term Potentiation in Area CA1

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.

Dendritic Spine Remodeling After Spinal Cord Injury Alters Neuronal Signal Processing

Central sensitization, a prolonged hyperexcitability of dorsal horn nociceptive neurons, is a major contributor to abnormal pain processing after spinal cord injury (SCI). Dendritic spines are micron-sized dendrite protrusions that can regulate the efficacy of synaptic transmission. Here we used a computational approach to study whether changes in dendritic spine shape, density, and distribution can individually, or in combination, adversely modify the input-output function of a postsynaptic neuron to create a hyperexcitable neuronal state. The results demonstrate that a conversion from thin-shaped to more mature, mushroom-shaped spine structures results in enhanced synaptic transmission and fidelity, improved frequency-following ability, and reduced inhibitory gating effectiveness. Increasing the density and redistributing spines toward the soma results in a greater probability of action potential activation. Our results demonstrate that changes in dendritic spine morphology, documented in previous studies on spinal cord injury, contribute to the generation of pain following SCI.