Activity-dependent Modulation Research Articles

Functional MRI of long-term potentiation: imaging network plasticity.

Neurons are able to express long-lasting and activity-dependent modulations of their synapses. This plastic property supports memory and conveys an extraordinary adaptive value, because it allows an individual to learn from, and respond to, changes in the environment. Molecular and physiological changes at the cellular level as well as network interactions are required in order to encode a pattern of synaptic activity into a long-term memory. While the cellular mechanisms linking synaptic plasticity to memory have been intensively studied, those regulating network interactions have received less attention. Combining high-resolution fMRI and in vivo electrophysiology in rats, we have previously reported a functional remodelling of long-range hippocampal networks induced by long-term potentiation (LTP) of synaptic plasticity in the perforant pathway. Here, we present new results demonstrating an increased bilateral coupling in the hippocampus specifically supported by the mossy cell commissural/associational pathway in response to LTP. This fMRI-measured increase in bilateral connectivity is accompanied by potentiation of the corresponding polysynaptically evoked commissural potential in the contralateral dentate gyrus and depression of the inactive convergent commissural pathway to the ipsilateral dentate. We review these and previous findings in the broader context of memory consolidation.

The Downregulation of Somatic A-Type K+Channels Requires the Activation of Synaptic NMDA Receptors in Young Hippocampal Neurons of Rats

The downregulation of A-type K+ channels (IA channels) accompanying enhanced somatic excitability can mediate epileptogenic conditions in mammalian central nervous system. As IA channels are dominantly targeted by dendritic and postsynaptic processings during synaptic plasticity, it is presumable that they may act as cellular linkers between synaptic responses and somatic processings under various excitable conditions. In the present study, we electrophysiologically tested if the downregulation of somatic IA channels was sensitive to synaptic activities in young hippocampal neurons. In primarily cultured hippocampal neurons (DIV 6~9), the peak of IA recorded by a whole-cell patch was significantly reduced by high KCl or exogenous glutamate treatment to enhance synaptic activities. However, the pretreatment of MK801 to block synaptic NMDA receptors abolished the glutamate-induced reduction of the IA peak, indicating the necessity of synaptic activation for the reduction of somatic IA. This was again confirmed by glycine treatment, showing a significant reduction of the somatic IA peak. Additionally, the gating property of IA channels was also sensitive to the activation of synaptic NMDA receptors, showing the hyperpolarizing shift in inactivation kinetics. These results suggest that synaptic LTP possibly potentiates somatic excitability via downregulating IA channels in expression and gating kinetics. The consequential changes of somatic excitability following the activity-dependent modulation of synaptic responses may be a series of processings for neuronal functions to determine outputs in memory mechanisms or pathogenic conditions.

Gap junctions

In vertebrates and invertebrates, signaling among neurons is most commonly mediated by chemical synapses. At these synapses neurotransmitter released by presynaptic neurons is detected by receptors on the postsynaptic neurons, leading to an influx of ions through the receptors themselves or through channels activated by intracellular signaling downstream of the receptors. But neurons can communicate with each other in a more direct way, by passing signals composed of small molecules and ions through pores called gap junctions. Gap junctions that transmit electrical signals are called electrical synapses. Unlike most chemical synapses, electrical synapses interact through axon-to-axon or dendrite-to-dendrite contacts. Found throughout the nervous system, they are probably best known for linking the relatively few inhibitory, GABAergic, neurons into large, effective networks within vertebrate brains. They are particularly important early in development before the formation of most chemical synapses, but recent work shows gap junctions play important roles in the adult nervous system, too. Gap junctions are sometimes thought to be mere passageways between cells. But, as recent work shows, their properties can be complex and surprising. Gap junctions help generate, propagate, and regulate neural oscillations, can filter electrical signals, and can be modulated in a variety of ways. Here we discuss recent work highlighting the diversity and importance of gap junctions throughout the nervous system.

White matter microstructure changes induced by motor skill learning utilizing a body machine interface

The purpose of this study is to identify white matter microstructure changes following bilateral upper extremity motor skill training to increase our understanding of learning-induced structural plasticity and enhance clinical strategies in physical rehabilitation. Eleven healthy subjects performed two visuo-spatial motor training tasks over 9 sessions (2–3 sessions per week). Subjects controlled a cursor with bilateral simultaneous movements of the shoulders and upper arms using a body machine interface. Before the start and within 2days of the completion of training, whole brain diffusion tensor MR imaging data were acquired. Motor training increased fractional anisotropy (FA) values in the posterior and anterior limbs of the internal capsule, the corona radiata, and the body of the corpus callosum by 4.19% on average indicating white matter microstructure changes induced by activity-dependent modulation of axon number, axon diameter, or myelin thickness. These changes may underlie the functional reorganization associated with motor skill learning.

Differential Roles of Postsynaptic Density-93 Isoforms in Regulating Synaptic Transmission

In the postsynaptic density of glutamatergic synapses, the discs large (DLG)-membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins coordinates a multiplicity of signaling pathways to maintain and regulate synaptic transmission. Postsynaptic density-93 (PSD-93) is the most variable paralog in this family; it exists in six different N-terminal isoforms. Probably because of the structural and functional variability of these isoforms, the synaptic role of PSD-93 remains controversial. To accurately characterize the synaptic role of PSD-93, we quantified the expression of all six isoforms in the mouse hippocampus and examined them individually in hippocampal synapses. Using molecular manipulations, including overexpression, gene knockdown, PSD-93 knock-out mice combined with biochemical assays, and slice electrophysiology both in rat and mice, we demonstrate that PSD-93 is required at different developmental synaptic states to maintain the strength of excitatory synaptic transmission. This strength is differentially regulated by the six isoforms of PSD-93, including regulations of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-active and inactive synapses, and activity-dependent modulations. Collectively, these results demonstrate that alternative combinations of N-terminal PSD-93 isoforms and DLG-MAGUK paralogs can fine-tune signaling scaffolds to adjust synaptic needs to regulate synaptic transmission.

Role of synaptic dynamics and heterogeneity in neuronal learning of temporal code

Temporal codes are believed to play important roles in neuronal representation of information. Neuronal ability to classify and learn temporal spiking patterns is thus essential for successful extraction and processing of information. Understanding neuronal learning of temporal code has been complicated, however, by the intrinsic stochasticity of synaptic transmission. Using a computational model of a learning neuron, the tempotron, we studied the effects of synaptic unreliability and short-term dynamics on the neuron's ability to learn spike timing rules. Our results suggest that such a model neuron can learn to classify spike timing patterns even with unreliable synapses, albeit with a significantly reduced success rate. We explored strategies to improve correct spike timing classification and found that firing clustered spike bursts significantly improves learning performance. Furthermore, rapid activity-dependent modulation of synaptic unreliability, implemented with realistic models of dynamic synapses, further improved classification of different burst properties and spike timing modalities. Neuronal models with only facilitating or only depressing inputs exhibited preference for specific types of spike timing rules, but a mixture of facilitating and depressing synapses permitted much improved learning of multiple rules. We tested applicability of these findings to real neurons by considering neuronal learning models with the naturally distributed input release probabilities found in excitatory hippocampal synapses. Our results suggest that spike bursts comprise several encoding modalities that can be learned effectively with stochastic dynamic synapses, and that distributed release probabilities significantly improve learning performance. Synaptic unreliability and dynamics may thus play important roles in the neuron's ability to learn spike timing rules during decoding.

Phosphorylation of the actin binding protein Drebrin at S647 is regulated by neuronal activity and PTEN.

Defects in actin dynamics affect activity-dependent modulation of synaptic transmission and neuronal plasticity, and can cause cognitive impairment. A salient candidate actin-binding protein linking synaptic dysfunction to cognitive deficits is Drebrin (DBN). However, the specific mode of how DBN is regulated at the central synapse is largely unknown. In this study we identify and characterize the interaction of the PTEN tumor suppressor with DBN. Our results demonstrate that PTEN binds DBN and that this interaction results in the dephosphorylation of a site present in the DBN C-terminus - serine 647. PTEN and pS647-DBN segregate into distinct and complimentary compartments in neurons, supporting the idea that PTEN negatively regulates DBN phosphorylation at this site. We further demonstrate that neuronal activity increases phosphorylation of DBN at S647 in hippocampal neurons in vitro and in ex vivo hippocampus slices exhibiting seizure activity, potentially by inducing rapid dissociation of the PTEN:DBN complex. Our results identify a novel mechanism by which PTEN is required to maintain DBN phosphorylation at dynamic range and signifies an unusual regulation of an actin-binding protein linked to cognitive decline and degenerative conditions at the CNS synapse.

Activity dependent modulation of synaptic transmission by presynaptic calcium stores: A dichotomy of short-term depression and facilitation

Ongoing electrical activity can initiate a positive feedback loop via Inositol Triphosphate Receptors (IP3Rs) and Ryanodine Receptors (RyRs) on the Endoplasmic Receptors (ER) that can lead to release of calcium from the ER. We investigated how the presence of this additional source of calcium in the presynaptic terminals in addition to the Voltage Dependent Calcium Channels (VDCCs) can regulate synaptic transmission. We carried out 3D Monte Carlo simulations of all the molecular interactions that govern transmitter release in a 1) Canonical CA3-CA1 synapse 2) A synapse reconstructed from serial section Transmission Electron Microscope images. The relatively simple geometry of CA3-CA1 synapses allows activity-dependent local calcium at the active zone and the related transmitter release profiles to be quantitatively analyzed. In paired-pulse stimulation, the presence of the molecular pathways that regulate the calcium stores increased the calcium buffering capacity of the synapse, which decreased release probability and enhanced paired-pulse facilitation. In contrast, a high-frequency stimulus could trigger the activation of presynaptic RyRs and Metabotropic Glutamate Receptors (mGluRs) leading to IP3 production and ultimately to release of calcium from the SER. IP3Rs and RyRs operated at a much slower time scale, on the order of seconds compared to the millisecond timescale of the VDCCs. This led to an increase in the basal level of intracellular calcium and enhanced transmitter release rates. In reconstructions of hippocampal neuropil, the ER appears in a majority of the presynaptic terminals in varying degrees of abundance. We further explored the functional implications of the range of ER geometries and therefore the calcium carrying capacity, observed in the synaptic ultrastructure and the effect of different arrangements between IP3Rs and VDCCs on synaptic plasticity. The synaptic ultrastructure precisely orchestrated the degree of facilitation and depression at the synapse and the existence of presynaptic calcium stores provided the synapse with an additional intrinsic time scale that could be regulated by activity.

Theoretical models of synaptic short term plasticity

Short term plasticity is a highly abundant form of rapid, activity-dependent modulation of synaptic efficacy. A shared set of mechanisms can cause both depression and enhancement of the postsynaptic response at different synapses, with important consequences for information processing. Mathematical models have been extensively used to study the mechanisms and roles of short term plasticity. This review provides an overview of existing models and their biological basis, and of their main properties. Special attention will be given to slow processes such as calcium channel inactivation and the effect of activation of presynaptic autoreceptors.

Increased serum brain-derived neurotrophic factor (BDNF) levels in patients with narcolepsy

Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness, sudden loss of muscle tone (cataplexy), fragmentation of nocturnal sleep and sleep paralysis. The symptoms of the disease strongly correlate with a reduction in hypocretin levels in CSF and a reduction in hypocretin neurons in hypothalamus in post-mortem tissue. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are important for activity-dependent neuronal function and synaptic modulation and it is considered that these mechanisms are important in sleep regulation. We hypothesized that serum levels of these factors are altered in patients with narcolepsy compared to healthy controls without sleep disturbances. Polysomnography data was obtained and serum BDNF and NGF levels measured using ELISA, while hypocretin was measured using RIA. Serum BDNF levels were significantly higher in narcolepsy patients than in healthy controls (64.2±3.9ng/ml vs. 47.3±2.6ng/ml, P<0.01), while there were no significant differences in NGF levels. As expected, narcolepsy patients had higher BMI compared to controls, but BMI did not correlate with the serum BDNF levels. The change in BDNF levels was not related to disease duration and sleep parameters did not correlate with BDNF in narcolepsy patients. The mechanisms behind the marked increase in BDNF levels in narcolepsy patients remain unknown.

Secreted Frizzled-Related Protein 3 Regulates Activity-Dependent Adult Hippocampal Neurogenesis

Adult neurogenesis, the process of generating mature neurons from adult neural stem cells, proceeds concurrently with ongoing neuronal circuit activity and is modulated by various physiological and pathological stimuli. The niche mechanism underlying the activity-dependent regulation of the sequential steps of adult neurogenesis remains largely unknown. Here, we report that neuronal activity decreases the expression of secreted frizzled-related protein 3 (sFRP3), a naturally secreted Wnt inhibitor highly expressed by adult dentate gyrus granule neurons. Sfrp3 deletion activates quiescent radial neural stem cells and promotes newborn neuron maturation, dendritic growth, and dendritic spine formation in the adult mouse hippocampus. Furthermore, sfrp3 reduction is essential for activity-induced adult neural progenitor proliferation and the acceleration of new neuron development. Our study identifies sFRP3 as an inhibitory niche factor from local mature dentate granule neurons that regulates multiple phases of adult hippocampal neurogenesis and suggests an interesting activity-dependent mechanism governing adult neurogenesis via the acute release of tonic inhibition.

Enhanced Intrinsic Excitability in Basket Cells Maintains Excitatory-Inhibitory Balance in Hippocampal Circuits

The dynamics of inhibitory circuits in the cortex is thought to rely mainly on synaptic modifications. We challenge this view by showing that hippocampal parvalbumin-positive basket cells (PV-BCs) of the CA1 region express long-term (>30min) potentiation of intrinsic neuronal excitability (LTP-IE(PV-BC)) upon brief repetitive stimulation of the Schaffer collaterals. LTP-IE(PV-BC) is induced by synaptic activation of metabotropic glutamate receptor subtype 5 (mGluR5) and mediated by the downregulation of Kv1 channel activity. LTP-IE(PV-BC) promotes spiking activity at the gamma frequency (∼35Hz) and facilitates recruitment of PV-BCs to balance synaptic and intrinsic excitation in pyramidal neurons. In conclusion, activity-dependent modulation of intrinsic neuronal excitability in PV-BCs maintains excitatory-inhibitory balance and thus plays a major role in the dynamics of hippocampal circuits.

Involvement of EphB1 Receptors Signalling in Models of Inflammatory and Neuropathic Pain

EphB receptors tyrosine kinases and ephrinB ligands were first identified as guidance molecules involved in the establishment of topographical mapping and connectivity in the nervous system during development. Later in development and into adulthood their primary role would switch from guidance to activity-dependent modulation of synaptic efficacy. In sensory systems, they play a role in both the onset of inflammatory and neuropathic pain, and in the establishment of central sensitisation, an NMDA-mediated form of synaptic plasticity thought to underlie most forms of chronic pain. We studied wild type and EphB1 knockout mice in a range of inflammatory and neuropathic pain models to determine 1), whether EphB1 expression is necessary for the onset and/or maintenance of persistent pain, regardless of origin; 2), whether in these models cellular and molecular changes, e.g. phosphorylation of the NR2B subunit of the NMDA receptor, increased c-fos expression or microglial activation, associated with the onset of pain, are affected by the lack of functional EphB1 receptors. Differences in phenotype were examined behaviourally, anatomically, biochemically and electrophysiologically. Our results establish firstly, that functional EphB1 receptors are not essential for the development of normal nociception, thermal or mechanical sensitivity. Secondly, they demonstrate a widespread involvement of EphB1 receptors in chronic pain. NR2B phosphorylation, c-fos expression and microglial activation are all reduced in EphB1 knockout mice. This last finding is intriguing, since microglial activation is supposedly triggered directly by primary afferents, therefore it was not expected to be affected. Interestingly, in some models of long-term pain (days), mechanical and thermal hyperalgesia develop both in wild type and EphB1 knockout mice, but recovery is faster in the latter, indicating that in particular models these receptors are required for the maintenance, rather than the onset of, thermal and mechanical hypersensitivity. This potentially makes them an attractive target for analgesic strategies.

Theoretical models of synaptic short term plasticity.

Short term plasticity is a highly abundant form of rapid, activity-dependent modulation of synaptic efficacy. A shared set of mechanisms can cause both depression and enhancement of the postsynaptic response at different synapses, with important consequences for information processing. Mathematical models have been extensively used to study the mechanisms and roles of short term plasticity. This review provides an overview of existing models and their biological basis, and of their main properties. Special attention will be given to slow processes such as calcium channel inactivation and the effect of activation of presynaptic autoreceptors.

Octopamine Neurons Mediate Flight-Induced Modulation of Visual Processing in Drosophila

Activity-dependent modulation of sensory systems has been documented in many organisms and is likely to be essential for appropriate processing of information during different behavioral states. However, the mechanisms underlying these phenomena remain poorly characterized. We investigated the role of octopamine neurons in the flight-dependent modulation observed in visual interneurons in Drosophila. The vertical system (VS) cells exhibit a boost in their response to visual motion during flight compared to quiescence. Pharmacological application of octopamine evokes responses in quiescent flies that mimic those observed during flight, and octopamine cells that project to the optic lobes increase in activity during flight. Using genetic tools to manipulate the activity of octopamine neurons, we find that they are both necessary and sufficient for the flight-induced visual boost. This study provides the first evidence that endogenous release of octopamine is involved in state-dependent modulation of visual interneurons in flies.

Fine-tuning synaptic plasticity by modulation of Ca V 2.1 channels with Ca 2+ sensor proteins

Modulation of P/Q-type Ca(2+) currents through presynaptic voltage-gated calcium channels (Ca(V)2.1) by binding of Ca(2+)/calmodulin contributes to short-term synaptic plasticity. Ca(2+)-binding protein-1 (CaBP1) and Visinin-like protein-2 (VILIP-2) are neurospecific calmodulin-like Ca(2+) sensor proteins that differentially modulate Ca(V)2.1 channels, but how they contribute to short-term synaptic plasticity is unknown. Here, we show that activity-dependent modulation of presynaptic Ca(V)2.1 channels by CaBP1 and VILIP-2 has opposing effects on short-term synaptic plasticity in superior cervical ganglion neurons. Expression of CaBP1, which blocks Ca(2+)-dependent facilitation of P/Q-type Ca(2+) current, markedly reduced facilitation of synaptic transmission. VILIP-2, which blocks Ca(2+)-dependent inactivation of P/Q-type Ca(2+) current, reduced synaptic depression and increased facilitation under conditions of high release probability. These results demonstrate that activity-dependent regulation of presynaptic Ca(V)2.1 channels by differentially expressed Ca(2+) sensor proteins can fine-tune synaptic responses to trains of action potentials and thereby contribute to the diversity of short-term synaptic plasticity.

Activity-Dependent Modulation of the Interaction between CaMKIIα and Abi1 and Its Involvement in Spine Maturation

Remodeling of dendritic spines through regulation of actin dynamics is a key event in activity-dependent structural plasticity. However, the molecular mechanism underlying this process is poorly understood. Here, we show that activity-dependent modulation of Abl interactor 1-Ca(2+)/calmodulin-dependent kinase IIα (Abi1-CaMKIIα) interaction, and thereby their activity, is important for regulation of spine morphology in cultured rat hippocampal neurons. Abi1 interacts with CaMKIIα at resting conditions through Abi1's tSNARE (target membrane-associated SNARE), which harbors striking homology with CaMKIIα regulatory domain. The interaction of the two proteins, Abi1 and CaMKIIα, results in their simultaneous inhibition, inhibition of CaMKIIα activity, and also inhibition of Abi1-dependent Rac activation. Their functional impediment is released when they dissociate from each other by calmodulin binding through glutamate receptor activation. Before dissociation, Abi1 is phosphorylated by CaMKIIα at serine 88, which may involve in regulation of Rac activation and spine maturation. Our results suggest that modulation of the interaction between Abi1 and CaMKIIα, through the glutamate receptor pathway, may be a molecular mechanism underlying activity-regulated structural plasticity in rat hippocamapal neurons.

Dopaminergic modulation of the hippocampal neuropil proteome identified by bioorthogonal noncanonical amino acid tagging (BONCAT)

Local protein synthesis and its activity-dependent modulation via dopamine receptor stimulation play an important role in synaptic plasticity - allowing synapses to respond dynamically to changes in their activity patterns. We describe here the metabolic labeling, enrichment, and MS-based identification of candidate proteins specifically translated in intact hippocampal neuropil sections upon treatment with the selective D1/D5 receptor agonist SKF81297. Using the noncanonical amino acid azidohomoalanine and click chemistry, we identified over 300 newly synthesized proteins specific to dendrites and axons. Candidates specific for the SKF81297-treated samples were predominantly involved in protein synthesis and synapse-specific functions. Furthermore, we demonstrate a dendrite-specific increase in proteins synthesis upon application of SKF81297. This study provides the first snapshot in the dynamics of the dopaminergic hippocampal neuropil proteome.

Modulation of Action Potential Trains in Rabbit Saphenous Nerve Unmyelinated Fibers

Usually, the main axon is assumed to faithfully conduct action potentials (APs). Recent data have indicated that neural processing can occur along the axonal path. However, the patterns and mechanisms of temporal coding are not clear. In the present study, single fiber recording was used to analyze activity-dependent modulation of AP trains in the main axons of C fibers in the rabbit saphenous nerve. Trains of 5 superthreshold electrical pulses at interstimulus intervals of 20 or 50 ms were applied to the nerve trunk for 200 s. The interspike intervals (ISIs) for these trains were compared to the input interstimulus intervals. Three basic types of C fibers were observed in response to repeated stimuli: first, the ISI between the first and second AP (ISI_1-2) of type 1 was longer than the interstimulus interval; second, the ISI_1-2 of type 2 showed wavelike fluctuations around the interstimulus interval, and third, the ISI_1-2 of type 3 exhibited shorter intervals for a long period. Furthermore, both 4-aminopyridine-sensitive potassium and hyperpolarization-activated cation currents were involved in the modulation of ISI_1-2 of train pulses. These data provide new evidence that multiple modes of neural conduction can occur along the main axons of C fibers.

Metabolic Pathways and Activity-Dependent Modulation of Glutamate Concentration in the Human Brain

Glutamate is one of the most versatile molecules present in the human brain, involved in protein synthesis, energy production, ammonia detoxification, and transport of reducing equivalents. Aside from these critical metabolic roles, glutamate plays a major part in brain function, being not only the most abundant excitatory neurotransmitter, but also the precursor for γ-aminobutyric acid, the predominant inhibitory neurotransmitter. Regulation of glutamate levels is pivotal for normal brain function, as abnormal extracellular concentration of glutamate can lead to impaired neurotransmission, neurodegeneration and even neuronal death. Understanding how the neuron-astrocyte functional and metabolic interactions modulate glutamate concentration during different activation status and under physiological and pathological conditions is a challenging task, and can only be tentatively estimated from current literature. In this paper, we focus on describing the various metabolic pathways which potentially affect glutamate concentration in the brain, and emphasize which ones are likely to produce the variations in glutamate concentration observed during enhanced neuronal activity in human studies.