Regulation Of Synaptic Efficacy Research Articles

Myosin Va-dependent Transport of NMDA Receptors in Hippocampal Neurons.

N-methyl-D-aspartate receptor (NMDAR) trafficking is a key process in the regulation of synaptic efficacy and brain function. However, the molecular mechanism underlying the surface transport of NMDARs is largely unknown. Here we identified myosin Va (MyoVa) as the specific motor protein that traffics NMDARs in hippocampal neurons. We found that MyoVa associates with NMDARs through its cargo binding domain. This association was increased during NMDAR surface transport. Knockdown of MyoVa suppressed NMDAR transport. We further demonstrated that Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates NMDAR transport through its direct interaction with MyoVa. Furthermore, MyoVa employed Rab11 family-interacting protein 3 (Rab11/FIP3) as the adaptor proteins to couple themselves with NMDARs during their transport. Accordingly, the knockdown of FIP3 impairs hippocampal memory. Together, we conclude that in hippocampal neurons, MyoVa conducts active transport of NMDARs in a CaMKII-dependent manner.

MicroRNA-34a Acutely Regulates Synaptic Efficacy in the Adult Dentate Gyrus In Vivo.

Activity-dependent synaptic plasticity involves rapid regulation of neuronal protein synthesis on a time-scale of minutes. miRNA function in synaptic plasticity and memory formation has been elucidated by stable experimental manipulation of miRNA expression and activity using transgenic approaches and viral vectors. However, the impact of rapid miRNA modulation on synaptic efficacy is unknown. Here, we examined the effect of acute (12 min), intrahippocampal infusion of a miR-34a antagonist (antimiR) on medial perforant path-evoked synaptic transmission in the dentate gyrus of adult anesthetised rats. AntimiR-34a infusion acutely depressed medial perforant path-evoked field excitatory post-synaptic potentials (fEPSPs). The fEPSP decrease was detected within 9 min of infusion, lasted for hours, and was associated with knockdown of antimiR-34a levels. AntimiR-34a-induced synaptic depression was sequence-specific; no changes were elicited by infusion of scrambled or mismatch control. The rapid modulation suggests that a target, or set of targets, is regulated by miR-34a. Western blot analysis of dentate gyrus lysates revealed enhanced expression of Arc, a known miR-34a target, and four novel predicted targets (Ctip2, PKI-1α, TCF4 and Ube2g1). Remarkably, antimiR-34a had no effect when infused during the maintenance phase of long-term potentiation. We conclude that miR-34a regulates basal synaptic efficacy in the adult dentate gyrus in vivo. To our knowledge, these in vivo findings are the first to demonstrate acute (< 9 min) regulation of synaptic efficacy in the adult brain by a miRNA.

Intermittent Hypoxia Disrupts Synaptic Long Term Depression

Long term potentiation (LTP), activity‐dependent synaptic strengthening, and long term depression (LTD), activity dependent synaptic attenuation, are two forms of synaptic plasticity whose underlying mechanisms permit flexibility in synaptic communication and serve as substrates for learning and memory. Intermittent hypoxia (IH), a hallmark of sleep apnea, is known to impair spatial learning and memory. The objective of this study is determine how LTP and LTD are affected by IH. We hypothesize that IH impedes efficacy of activity dependent synaptic plasticity in the hippocampus, a brain structure important to learning and memory. We examined in vitro LTP and LTD in hippocampal brain slices following IH exposure. Electrophysiological recordings showed that LTP in area CA1 could be evoked in control and IH exposed groups, yet the magnitude of LTP following IH was decreased (LTP: control 184.72±15.93% vs. IH 145.35±6.34% baseline) . While LTD could be elicited in the control group (63.31±3.03% baseline), LTD could not be evoked from the IH exposed group (104.18±3.44% baseline). Although IH impacted both forms of long term synaptic plasticity, this was not accompanied by differences in paired‐pulse facilitation, indicating that short‐term plasticity was unaffected by IH. These findings demonstrate that IH affects mechanisms of activity‐dependent regulation of synaptic efficacy, which may involve IH‐dependent changes in NMDA receptor contribution to these phenomena. Our findings further contribute to understanding potential neurophysiological changes that may decrease the threshold for cognitive decline associated with sleep apnea.Support or Funding InformationThis work was supported by NIH R01 NS10742101 (AJG).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Neuronal Ca2+ signalling at rest and during spontaneous neurotransmission

Action potential driven neuronal signalling drives several electrical and biochemical processes in the nervous system. However, neurons can maintain synaptic communication and signalling under resting conditions independently of activity. Importantly, these processes are regulated by Ca2+ signals that occur at rest. Several studies have suggested that opening of voltage-gated Ca2+ channels near resting membrane potentials, activation of NMDA receptors in the absence of depolarization or Ca2+ release from intracellular stores can drive neurotransmitter release as well as subsequent signalling in the absence of action potentials. Interestingly, recent studies have demonstrated that manipulation of resting neuronal Ca2+ signalling yielded pronounced homeostatic synaptic plasticity, suggesting a critical role for this resting form of signalling in regulation of synaptic efficacy and neuronal homeostasis. Given their robust impact on synaptic efficacy and neuronal signalling, neuronal resting Ca2+ signals warrant further mechanistic analysis that includes the potential role of store-operated Ca2+ entry in these processes.

Neuromodulation influences synchronization and intrinsic read-out

Background: The roles of neuromodulation in a neural network, such as in a cortical microcolumn, are still incompletely understood. Methods: (a) Neuromodulation influences neural processing by presynaptic and postsynaptic regulation of synaptic efficacy. Synaptic efficacy modulation can be an effective way to rapidly alter network density and topology. We show that altering network topology and density, will affect spike synchronization. Fast synaptic efficacy modulation may therefore influence the amount of correlated spiking in a network. (b) Neuromodulation also affects ion channel regulation for intrinsic excitability, which alters the neuron’s activation function. Results: We show that synchronization in a network influences the read-out of these intrinsic properties. Highly synchronous input drives neurons, such that differences in intrinsic properties disappear, while asynchronous input lets intrinsic properties determine output behavior. Thus, altering network topology can alter the balance between intrinsically vs. synaptically driven network activity. Conclusion: We conclude that neuromodulation may allow a network to shift between a more synchronized transmission mode and a more asynchronous intrinsic read-out mode. This has significant implications for our understanding of the flexibility of cortical computations.

Cortical slow wave activity correlates with striatal synaptic strength in normal but not in Parkinsonian rats

Urethane-induced cortical slow wave activity (SWA) spreads into the basal ganglia in dopamine (DA)-depleted rat models of Parkinson's disease (PD). During physiological sleep, SWA is powerfully expressed at the beginning of night and progressively reduced during sleep-time reflecting the sleep need. However, its underlying slow oscillations may contribute directly to modulate cortical plasticity.In order to determine the impact of the SWA on synaptic strength and its interplay with DA, we simultaneously recorded the electrocorticogram (ECoG) and the corticocortical- and corticostriatal-evoked potentials (CC-EPs, CS-EPs) during eight hours of robust urethane-induced SWA in both normal and PD animals. A subgroup of PD rats was assessed with repetitive apomorphine (APO) administrations.Normal animals showed a progressive reduction of SWA power during urethane-induced SWA. Compared to normal animals, PD animals showed lower SWA power at the start of anesthesia without a significant reduction over time. Accordingly, synaptic strength measured by CC- and CS-EP amplitudes decreased in normal but not in Parkinsonian rats. The PD animals treated with APO showed a CS-EP amplitude reduction comparable to normal animals. Interestingly, SWA power directly correlated with CS-EP amplitude in normal animals.These data support the hypothesis that cortical SWA is directly associated with the regulation of synaptic efficacy in which DA exerts a crucial role.

Modulation of Synaptic Plasticity in the Cortex Needs to Understand All the Players

The prefrontal cortex (PFC) is involved in cognitive tasks such as working memory, decision making, risk assessment and regulation of attention. These functions performed by the PFC are supposed to rely on rhythmic electrical activity generated by neuronal network oscillations determined by a precise balance between excitation and inhibition balance (E/I balance) resulting from the coordinated activities of recurrent excitation and feedback and feedforward inhibition. Functional alterations in PFC functions have been associated with cognitive deficits in several pathologies such as major depression, anxiety and schizophrenia. These pathological situations are correlated with alterations of different neurotransmitter systems (i.e., serotonin (5-HT), dopamine (DA), acetylcholine…) that result in alterations of the E/I balance. The aim of this review article is to cover the basic aspects of the regulation of the E/I balance as well as to highlight the importance of the complementarity role of several neurotransmitters in the modulation of the plasticity of excitatory and inhibitory synapses. We illustrate our purpose by recent findings that demonstrate that 5-HT and DA cooperate to regulate the plasticity of excitatory and inhibitory synapses targeting layer 5 pyramidal neurons (L5PyNs) of the PFC and to fine tune the E/I balance. Using a method based on the decomposition of the synaptic conductance into its excitatory and inhibitory components, we show that concomitant activation of D1-like receptors (D1Rs) and 5-HT1ARs, through a modulation of NMDA receptors, favors long term potentiation (LTP) of both excitation and inhibition and consequently does not modify the E/I balance. We also demonstrate that activation of D2-receptors requires functional 5-HT1ARs to shift the E-I balance towards more inhibition and to favor long term depression (LTD) of excitatory synapses through the activation of glycogen synthase kinase 3β (GSK3β). This cooperation between different neurotransmitters is particularly relevant in view of pathological situations in which alterations of one neurotransmitter system will also have consequences on the regulation of synaptic efficacy by other neurotransmitters. This opens up new perspectives in the development of therapeutic strategies for the pharmacological treatment of neuronal disorders.

Homeostatic regulation of brain functions by endocannabinoid signaling.

Homeostatic regulation of brain functions by endocannabinoid signaling.

Neuronal plasticity during sleep slow wave oscillations

Sleep is critical for regulation of synaptic efficacy, consolidation of memories and learning. It has been proposed that synaptic plasticity associated with sleep rhythms could contribute to consolidation of memories acquired during wakefulness. It was suggested that in the active state of sleep slow wave oscillation, the hippocampal formation activates latent memories stored in the neocortex (replay) and induce permanent changes in synaptic conductances. In this study, we present a thalamocortical network model of the slow-wave sleep activity characterized by repeatable (< 1 Hz) transitions between active (Up) and silent (Down) states of the network. The model consisted a layer of thalamic relay (TC) and reticular (RE) neurons in the thalamus as well as a model of cortical column with pyramidal neurons and inhibitory interneurons. All neurons were modeled based on the Hodgkin-Huxley kinetics. Spike-timing dependent synaptic plasticity was implemented to regulate synaptic efficacy. The slow oscillation was driven by intracortical dynamics; active states were initiated by the spontaneous miniature synaptic releases at different network sites [1] and propagated within the cortical network. The properties of slow oscillations depended on the intrinsic conductances, miniature synaptic releases, and the synaptic strength. In agreement with previous experimental studies, transition from the active to the silent state occurred more synchronously than the active state initiation. We found that the pattern of the active state propagation depended on the spatiotemporal pattern of activity on the previous cycle of slow oscillation and could be influenced by external input. Because of the refractoriness properties of the network, a probability of the next active state initiation was higher for the network site that initiated activity at the previous cycle. Furthermore, even weak external stimulation delivered to the network results in increase probability of up-state induction at the stimulation location. This suggests that spatially and temporally sparse hippocampal input could influence the spatiotemporal pattern of slow oscillation. Location of the initiation site and the pattern of active state propagation determined the relative timing of spiking in cortical neurons. When spike-time dependent synaptic plasticity (STDP) was implemented, there was a net decrease in synaptic strengths and, at the same time, an increase in the strength of specific synapses which were associated with the sequence replay. The change in synaptic weights between any two neurons was determined by the direction of active state propagation and by the distance between the neurons. Our study propose a mechanism of how interaction between cortically generated slow waves and sparse external input, possibly representing input from hippocampal formation, may lead to reorganization of synaptic strength during stage 3/4 sleep.

Differential gating of dendritic spikes by compartmentalized inhibition

Differential gating of dendritic spikes by compartmentalized inhibition

Spike-Timing-Dependent Potentiation of Sensory Surround in the Somatosensory Cortex Is Facilitated by Deprivation-Mediated Disinhibition

Functional maps in the cerebral cortex reorganize in response to changes in experience, but the synaptic underpinnings remain uncertain. Here, we demonstrate that layer (L) 2/3 pyramidal cell synapses in mouse barrel cortex can be potentiated upon pairing of whisker-evoked postsynaptic potentials (PSPs) with action potentials (APs). This spike-timing-dependent long-term potentiation (STD-LTP) was only effective for PSPs evoked by deflections of a whisker in the neuron's receptive field center, and not its surround. Trimming of all except two whiskers rapidly opened the possibility to drive STD-LTP by the spared surround whisker. This facilitated STD-LTP was associated with a strong decrease in the surrounding whisker-evoked inhibitory conductance and partially occluded picrotoxin-mediated LTP facilitation. Taken together, our data demonstrate that sensory deprivation-mediated disinhibition facilitates STD-LTP from the sensory surround, which may promote correlation- and experience-dependent expansion of receptive fields.

EphA Signaling Promotes Actin-based Dendritic Spine Remodeling through Slingshot Phosphatase

Actin cytoskeletal remodeling plays a critical role in transforming the morphology of subcellular structures across various cell types. In the brain, restructuring of dendritic spines through actin cytoskeleletal reorganization is implicated in the regulation of synaptic efficacy and the storage of information in neural circuits. However, the upstream pathways that provoke actin-based spine changes remain only partly understood. Here we show that EphA receptor signaling remodels spines by triggering a sequence of events involving actin filament rearrangement and synapse/spine reorganization. Rapid EphA signaling over minutes activates the actin filament depolymerizing/severing factor cofilin, alters F-actin distribution in spines, and causes transient spine elongation through the phosphatases slingshot 1 (SSH1) and calcineurin/protein phosphatase 2B (PP2B). This early phase of spine extension is followed by synaptic reorganization events that take place over minutes to hours and involve the relocation of pre/postsynaptic components and ultimately spine retraction. Thus, EphA receptors utilize discrete cellular and molecular pathways to promote actin-based structural plasticity of excitatory synapses.

Parallel computational subunits in dentate granule cells generate multiple place fields

A fundamental question in understanding neuronal computations is how dendritic events influence the output of the neuron. Different forms of integration of neighbouring and distributed synaptic inputs, isolated dendritic spikes and local regulation of synaptic efficacy suggest that individual dendritic branches may function as independent computational subunits. In the present paper, we study how these local computations influence the output of the neuron. Using a simple cascade model, we demonstrate that triggering somatic firing by a relatively small dendritic branch requires the amplification of local events by dendritic spiking and synaptic plasticity. The moderately branching dendritic tree of granule cells seems optimal for this computation since larger dendritic trees favor local plasticity by isolating dendritic compartments, while reliable detection of individual dendritic spikes in the soma requires a low branch number. Finally, we demonstrate that these parallel dendritic computations could contribute to the generation of multiple independent place fields of hippocampal granule cells.

Learning to Encode Timing: Mechanisms of Plasticity in the Auditory Brainstem

Mechanisms of plasticity have traditionally been ascribed to higher-order sensory processing areas such as the cortex, whereas early sensory processing centers have been considered largely hard-wired. In agreement with this view, the auditory brainstem has been viewed as a nonplastic site, important for preserving temporal information and minimizing transmission delays. However, recent groundbreaking results from animal models and human studies have revealed remarkable evidence for cellular and behavioral mechanisms for learning and memory in the auditory brainstem.

Regulation of Synaptic Efficacy in Hypocretin/Orexin-Containing Neurons by Melanin Concentrating Hormone in the Lateral Hypothalamus

The lateral hypothalamus (LH) is a central hub that integrates inputs from, and sends outputs to, many other brain areas. Two groups of neurons in the LH, expressing hypocretin/orexin or melanin concentrating hormone (MCH), have been shown to participate in sleep regulation, energy homeostasis, drug addiction, motor regulation, stress response, and social behaviors. The elucidation of crosstalk between these two systems is essential to understand these behaviors and functions because there is evidence that there are reciprocal innervations between hypocretin/orexin and MCH neurons. In this study, we used MCH receptor-1 knock-out (MCHR1 KO) and wild-type (WT) mice expressing green fluorescent protein in hypocretin/orexin-containing neurons to examine the hypothesis that MCH modulates hypocretin/orexin-mediated effects on behavioral state and synaptic transmission in the LH. In MCHR1 KO mice, the efficacy of glutamatergic synapses on hypocretin/orexin neurons is potentiated and hypocretin-1-induced action potential firing is facilitated, potentially explaining an increased effect of modafinil observed in MCHR1 KO mice. In wild-type mice with intact MCHR1 signaling, MCH significantly attenuated the hypocretin-1-induced enhancement of spike frequency in hypocretin/orexin neurons. The MCH effect was dose dependent, pertussis toxin sensitive, and was abolished in MCHR1 KO mice. Consistent with this effect, MCH attenuated hypocretin-1-induced enhancement of the frequency of miniature EPSCs in hypocretin/orexin neurons. These data from MCHR1 KO and WT mice demonstrate a novel interaction between these two systems, implying that MCH may exert a unique inhibitory influence on hypocretin/orexin signaling as a way to fine-tune the output of the LH.

A Precisely Timed Asynchronous Pattern of ON and OFF Retinal Ganglion Cell Activity during Propagation of Retinal Waves

Patterns of coordinated spontaneous activity have been proposed to guide circuit refinement in many parts of the developing nervous system. It is unclear, however, how such patterns, which are thought to indiscriminately synchronize nearby cells, could provide the cues necessary to segregate functionally distinct circuits within overlapping cell populations. Here, we report that glutamatergic retinal waves possess a substructure in the bursting of neighboring retinal ganglion cells with opposite light responses (ON or OFF). Within a wave, cells fire repetitive nonoverlapping bursts in a fixed order: ON before OFF. This pattern is absent from cholinergic waves, which precede glutamate-dependent activity, providing a developmental sequence of distinct activity-encoded cues. Asynchronous bursting of ON and OFF retinal ganglion cells depends on inhibition between these parallel pathways. Similar asynchronous activity patterns could arise throughout the nervous system, as inhibition matures and might help to separate connections of functionally distinct subnetworks.

Cannabinoid regulation in identified synapse of terrestrial snail

In the terrestrial snail a direct monosynaptic glutamatergic connection between the primary sensory neuron and a premotor interneuron involved in withdrawal behaviour can be functionally identified using electrophysiological techniques. We investigated the involvement of cannabinoids in regulation of this synaptic contact. The results demonstrate that the specific binding sites for agonists to mammalian type 1 cannabinoid receptors (CB1Rs) exist in the snail's nervous system. Application of a synthetic cannabinoid agonist anandamide selectively changed the efficacy of synaptic contacts between the identified neurons. A decrease in the long-term synaptic facilitation of the synaptic contact elicited by high-frequency nerve tetanization in the presence of cannabinoid agonist anandamide was observed, suggesting a possible role of endocannabinoids in regulation of plasticity at this synaptic site. The selective antagonist of CB1Rs [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] AM251 bath application was changing the efficacy of the synaptic contact only when the postsynaptic neuron had been intracellularly activated before its application. This observation implies an involvement of endocannabinoids in plasticity phenomena induced by activity in the postsynaptic target. Additional support of endocannabinoid involvement in synaptic function at this site was given by experiments in which AM251 blocked the short-term suppression of synaptic excitation evoked by low-frequency nerve tetanization, a phenomenon qualitatively similar to cannabinoid-dependent synaptically evoked suppression of excitation demonstrated in the mammalian nervous system. The results of the present study suggest an involvement of cannabinoids in the regulation of synaptic efficacy. Further, anandamide could be a candidate for an endogenous neuromessenger involved in plasticity processes.

Distinct Frequency-Dependent Regulation of Nerve Terminal Excitability and Synaptic Transmission by IA and IK Potassium Channels Revealed by Drosophila Shaker and Shab Mutations

Regulation of synaptic efficacy by nerve terminal excitability has not been extensively studied. We performed genetic and pharmacological dissections for presynaptic actions of K+ channels in Drosophila neuromuscular transmission by using electrophysiological and optical imaging techniques. Current understanding of the roles of the Shab IK channel and its mammalian Kv2 counterparts is relatively poor, as compared with that for Shaker IA channels and their Kv1 homologues. Our results revealed the striking effect of Shab mutations during high-frequency synaptic activity, as well as a functional division in synaptic regulation between the Shaker and Shab channels. Shaker channels control the basal level of release, indicated by a response to single nerve stimulation, whereas Shab channels regulate repetitive synaptic activities. These observations highlight the crucial control of nerve terminal excitability by Shaker and Shab channels to confer temporal patterns of synaptic transmission and suggest the potential participation of these channels, along with the transmitter release machinery, in activity-dependent synaptic plasticity.

Spatiotemporal Specificity of Neuronal Activity Directs the Modification of Receptive Fields in the Developing Retinotectal System

The precise temporal relation between pre- and postsynaptic activity modulates the strength of synaptic connections. Despite its extensive characterization in vivo and in vitro, the degree to which spike timing-dependent plasticity can shape receptive field properties is unclear. We use in vivo patch-clamp recordings of tectal neurons in developing Xenopus tadpoles to control the precise timing of action potentials with respect to the arrival of a subset of visual inputs evoked by local light stimulation on the retina. The pattern of visual inputs onto a tectal neuron was tracked over time by rapid reverse correlation mapping of receptive fields. Spike timing-dependent potentiation or depression of a subset of synapses reliably shifts the spatial receptive fields toward or away from the trained subregion of visual space, respectively. These results demonstrate that natural patterns of activity evoked by sensory stimuli play an instructive role in the developing nervous system.

Place-Selective Firing of CA1 Pyramidal Cells during Sharp Wave/Ripple Network Patterns in Exploratory Behavior

We observed sharp wave/ripples (SWR) during exploration within brief (<2.4 s) interruptions of or during theta oscillations. CA1 network responses of SWRs occurring during exploration (eSWR) and SWRs detected in waking immobility or sleep were similar. However, neuronal activity during eSWR was location dependent, and eSWR-related firing was stronger inside the place field than outside. The eSPW-related firing increase was stronger than the baseline increase inside compared to outside, suggesting a "supralinear" summation of eSWR and place-selective inputs. Pairs of cells with similar place fields and/or correlated firing during exploration showed stronger coactivation during eSWRs and subsequent sleep-SWRs. Sequential activation of place cells was not required for the reactivation of waking co-firing patterns; cell pairs with symmetrical cross-correlations still showed reactivated waking co-firing patterns during sleep-SWRs. We suggest that place-selective firing during eSWRs facilitates initial associations between cells with similar place fields that enable place-related ensemble patterns to recur during subsequent sleep-SWRs.