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Neuroscience_topics
Neuroscience: CNS disease, pain, brain research, ion channels, synaptic transmission, channelopathies, neuronal network
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The mechanisms and functions of spontaneous neurotransmitter release

The mechanisms and functions of spontaneous neurotransmitter release | Neuroscience_topics | Scoop.it

Fast synaptic communication in the brain requires synchronous vesicle fusion that is evoked by action potential-induced Ca2+ influx. However, synaptic terminals also release neurotransmitters by spontaneous vesicle fusion, which is independent of presynaptic action potentials. A functional role for spontaneous neurotransmitter release events in the regulation of synaptic plasticity and homeostasis, as well as the regulation of certain behaviours, has been reported. In addition, there is evidence that the presynaptic mechanisms underlying spontaneous release of neurotransmitters and their postsynaptic targets are segregated from those of evoked neurotransmission. These findings challenge current assumptions about neuronal signalling and neurotransmission, as they indicate that spontaneous neurotransmission has an autonomous role in interneuronal communication that is distinct from that of evoked release.(...) -  by Ege T. Kavalali,, Nature Reviews Neuroscience,  16, 5–16 (2015)

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GABA actions and ionic plasticity in epilepsy

GABA actions and ionic plasticity in epilepsy | Neuroscience_topics | Scoop.it
[Review] Highlights:- Ionic plasticity of GABA signaling relies on short-term and long term changes in EGABA-  Cl− transport and carboanhydrases play a key role in ionic plasticity and epilepsy.

- GABAergic transmission has both seizure-suppressing and seizure-promoting effects.

- TrkB and calpain act on GABA signaling to coordinate the process of epileptogenesis.

- GABA signaling has context-specific and age-specific effects in health and disease.

- by Kaila Kai et al., Current Opinion in Neurobiology, Volume 26, June 2014, Pages 34–41

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Therapeutic potential of NaV1.1 activators

Highlights:- NaV1.1 is the major sodium current in specific inhibitory interneurons.- Interneuronal dysfunction is linked to epilepsies, schizophrenia, and AD.- NaV1.1 plays a modest role in excitatory neurons.- Selective NaV1.1 activators may hold great potential as a novel treatment paradigm.

By Jensen HS et al.,  Trends in Pharmacological Sciences, Volume 35, Issue 3, p113–118, March 2014

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Control of neuronal voltage-gated calcium ion channels from RNA to protein

[Review] Highlights:
  • How many different voltage-gated calcium (CaV) channels are there and should one care?
  • All mammalian Cacna1 genes have the potential to generate hundreds of CaV channels.
  • Cell specific mechanisms control CaV channel function at RNA and protein levels according to cell type.
  • Cell specific protein–protein interactions control subcellular CaV channel trafficking and function.
  • Cell specific and subcellular expression patterns of CaV isoforms are important for disease and treatment development.

(...) - by Lipscombe D et al., Trends in Neurosciences, available online 30 July 2013

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Adenosine receptors as drug targets - what are the challenges?

[Review] Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors — either directly or indirectly — have now entered the clinic. However, only one adenosine receptor-specific agent — the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma) — has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges.(...) - by Chen JF et al., Nature Reviews Drug Discovery, 12265-286 (April 2013)

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- Biophysical mechanisms regulating AMPA receptor accumulation at synapses

- Biophysical mechanisms regulating AMPA receptor accumulation at synapses | Neuroscience_topics | Scoop.it
Controlling the number of AMPA receptors at synapses is fundamental for fast synaptic transmission as well as for long term adaptations in synaptic strength. In this review, we examine the biophysical mechanisms implicated in regulating AMPAR levels at the cell surface and at synapses. We first describe the structure and function of AMPARs, as well as their interactions with various proteins regulating their traffic and function. Second we review the vesicular trafficking mechanism involving exocytosis and endocytosis, by which AMPARs reach the cell surface and are internalized, respectively. Third, we examine the properties of lateral diffusion of AMPARs and their trapping at post-synaptic densities. Finally, we discuss how these two parallel mechanisms are integrated in time and space to control changes in synaptic AMPAR levels in response to plasticity protocols. This review highlights the important role of the extra-synaptic AMPAR pool, which makes an obligatory link between vesicular trafficking and trapping or release at synapses. - By Czondor k & Thoumine O, Brain Research BulletinVolume 93, April 2013, Pages 57–68
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Signalling bias in new drug discovery: detection, quantification and therapeutic impact

Agonists of seven-transmembrane receptors, also known as G protein-coupled receptors (GPCRs), do not uniformly activate all cellular signalling pathways linked to a given seven-transmembrane receptor (a phenomenon termed ligand or agonist bias); this discovery has changed how high-throughput screens are designed and how lead compounds are optimized for therapeutic activity. The ability to experimentally detect ligand bias has necessitated the development of methods for quantifying agonist bias in a way that can be used to guide structure–activity studies and the selection of drug candidates. Here, we provide a viewpoint on which methods are appropriate for quantifying bias, based on knowledge of how cellular and intracellular signalling proteins control the conformation of seven-transmembrane receptors. We also discuss possible predictions of how biased molecules may perform in vivo, and what potential therapeutic advantages they may provide. (...) - by Kenakin T. & Christopoulos A.Nature Reviews Drug Discovery 12205-216 (March 2013)

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[Review] TRPs in the Brain

[Review] TRPs in the Brain | Neuroscience_topics | Scoop.it

[Abstract] The Transient receptor potential (TRP) family of cation channels is a large protein family, which is mainly structurally uniform. Proteins consist typically of six transmembrane domains and mostly four subunits are necessary to form a functional channel. Apart from this, TRP channels display a wide variety of activation mechanisms (ligand binding, G-protein coupled receptor dependent, physical stimuli such as temperature, pressure, etc.) and ion selectivity profiles (from highly Ca2+ selective to non-selective for cations). They have been described now in almost every tissue of the body, including peripheral and central neurons. Especially in the sensory nervous system the role of several TRP channels is already described on a detailed level. This review summarizes data that is currently available on their role in the central nervous system. TRP channels are involved in neurogenesis and brain development, synaptic transmission and they play a key role in the development of several neurological diseases. - by Vennekens R et al., Reviews of Physiology, Biochemistry and Pharmacology Volume 163, 2012, pp 27-64 

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Jim Siders's curator insight, February 11, 2013 1:43 PM

Hmmmm.......getting deeper

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Autaptic self-inhibition of cortical GABAergic neurons: Synaptic narcissism or useful introspection?

Autaptic self-inhibition of cortical GABAergic neurons: Synaptic narcissism or useful introspection? | Neuroscience_topics | Scoop.it
Highlights: 

-  Specific connectivity patterns between interneurons and excitatory cells.

- Cortical disinhibition is necessary for behavioral functions.

- Cortical disinhibition is provided by specific interneuron–interneuron connections.

- Autaptic self-inhibition of PV cells: a very efficient disinhibition stratagem.

- A dual role of autaptic inhibition in temporally coordinating PV basket cells. (...) - by Deleuze C et al., Current Opinion in Neurobiology, Volume 26, June 2014, Pages 64–71

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Neuronal Voltage-Gated Calcium Channels: Structure, Function, and Dysfunction

Neuronal Voltage-Gated Calcium Channels: Structure, Function, and Dysfunction | Neuroscience_topics | Scoop.it

[Review] Voltage-gated calcium channels are the primary mediators of depolarization-induced calcium entry into neurons. There is great diversity of calcium channel subtypes due to multiple genes that encode calcium channel α1 subunits, coassembly with a variety of ancillary calcium channel subunits, and alternative splicing. This allows these channels to fulfill highly specialized roles in specific neuronal subtypes and at particular subcellular loci. While calcium channels are of critical importance to brain function, their inappropriate expression or dysfunction gives rise to a variety of neurological disorders, including, pain, epilepsy, migraine, and ataxia. This Review discusses salient aspects of voltage-gated calcium channel function, physiology, and pathophysiology. - by Simms BA & Zamponi GW, Neuron, Volume 82, Issue 1, p24–45, 2 April 2014

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Modulation of NMDA receptor at the synapse: Promising therapeutic interventions in disorders of the nervous system

Modulation of NMDA receptor at the synapse: Promising therapeutic interventions in disorders of the nervous system | Neuroscience_topics | Scoop.it

[Review] There is general agreement that excessive activation of N-methyl-D-aspartate (NMDA) receptors plays a key role in mediating at least some aspects of synaptic dysfunction in several central nervous system disorders. On this view, in the last decades, research focused on the discovery of different compounds able to reduce NMDA receptor activity, such as classical and/or subunit-specific antagonists. However, the increasing body of knowledge on specific signaling pathways downstream NMDA receptors led to the identification of new pharmacological targets for NMDA receptor-related pathological conditions. Moreover, besides over-activation, several studies indicated that also abnormal NMDA receptor trafficking, resulting in the modification of the receptor subunit composition at the synapse, has a major role in the pathogenesis of several brain disorders. For this reason, the discovery of the molecular mechanisms regulating the abundance of synaptic versus extra-synaptic NMDA receptors as well as the activation of the specific signaling pathways downstream the different NMDA receptor subtypes is needed for the development of novel therapeutic approaches for NMDA receptor-dependent synaptic dysfunction. (...) - Mellone M. & Gardoni FEuropean Journal of Pharmacology

Volume 719, Issues 1–3, 5 November 2013, Pages 75–83

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[Review] Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction

Epilepsy is a prevalent neurological disorder associated with significant morbidity and mortality, but the only available drug therapies target its symptoms rather than the underlying cause. The process that links brain injury or other predisposing factors to the subsequent emergence of epilepsy is termed epileptogenesis. Substantial research has focused on elucidating the mechanisms of epileptogenesis so as to identify more specific targets for intervention, with the hope of preventing epilepsy before seizures emerge. Recent work has yielded important conceptual advances in this field. We suggest that such insights into the mechanisms of epileptogenesis converge at the level of cortical circuit dysfunction. - by Goldberg EM & Coulter DANature Reviews Neuroscience 14337-349 (May 2013)

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The axon as a unique computational unit in neurons

The axon as a unique computational unit in neurons | Neuroscience_topics | Scoop.it

[Review] In the mammalian cortex, axons are highly ramified and link an enormous number of neurons over large distances. The conventional view assumes that action potentials (APs) are initiated at the axon initial segment in an all-or-none fashion and are then self-propagated orthodromically along axon collaterals without distortion of the AP waveform. By contrast, recent experimental results suggest that the axonal AP waveform can be modified depending on the activation states of the ion channels and receptors on axonal cell membranes. This AP modulation can regulate neurotransmission to postsynaptic neurons. In addition, the latest studies have provided evidence that cortical axons can integrate somatic burst firings and promote activity-dependent ectopic AP generation, which may underlie the oscillogenesis of fast rhythmic network activity. These seminal observations indicate that axons can perform diverse functional operations that extend beyond the prevailing model of axon physiology. (...) - by Sasaki TNeuroscience ResearchVolume 75, Issue 2, February 2013, Pages 83–88

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Current status of chemokines in the adult CNS

Current status of chemokines in the adult CNS | Neuroscience_topics | Scoop.it

Highlights

  • A better understanding of the role of chemokines and their receptors in the CNS in addition to the immune system.
  • This review focuses on recent data about three couples CXCL12/CXCR4, CCL2/CCR2, and CX3CL1/CX3CR1 in the adult CNS.
  • Description of their cellular expression, distributions, and roles in neurotransmission and neuromodulation.
  • This review summarizes current evidence on the role of these chemokine systems in the pathogenesis of CNS disorders.

by Réaux-Le Goazigo A. et al.Progress in Neurobiology, In Press, Available online 27 February 2013


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[Review] Kynurenines in the CNS: recent advances and new questions

[Review] Kynurenines in the CNS: recent advances and new questions | Neuroscience_topics | Scoop.it

Various pathologies of the central nervous system (CNS) are accompanied by alterations in tryptophan metabolism. The main metabolic route of tryptophan degradation is the kynurenine pathway; its metabolites are responsible for a broad spectrum of effects, including the endogenous regulation of neuronal excitability and the initiation of immune tolerance. This Review highlights the involvement of the kynurenine system in the pathology of neurodegenerative disorders, pain syndromes and autoimmune diseases through a detailed discussion of its potential implications in Huntington's disease, migraine and multiple sclerosis. The most effective preclinical drug candidates are discussed and attention is paid to currently under-investigated roles of the kynurenine pathway in the CNS, where modulation of kynurenine metabolism might be of therapeutic value. - by Vécsei L et al.Nature Reviews Drug Discovery 1264-82 (January 2013) | doi:10.1038/nrd3793

Julien Hering, PhD's insight:

Interesting review about the kynurenine system invovled in neurodegenerative disorders, pain syndromes and autoimmune disease in CNS. 

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HCN2 ion channels: an emerging role as the pacemakers of pain

HCN2 ion channels: an emerging role as the pacemakers of pain | Neuroscience_topics | Scoop.it

Acute nociceptive pain is caused by the direct action of a noxious stimulus on pain-sensitive nerve endings, whereas inflammatory pain (both acute and chronic) arises from the actions of a wide range of inflammatory mediators released following tissue injury. Neuropathic pain, which is triggered by nerve damage, is often considered to be very different in its origins, and is particularly difficult to treat effectively. Here we review recent evidence showing that members of the hyperpolarization-activated cyclic nucleotide-modulated (HCN) ion channel family – better known for their role in the pacemaker potential of the heart – play important roles in both inflammatory and neuropathic pain. Deletion of the HCN2 isoform from nociceptive neurons abolishes heat-evoked inflammatory pain and all aspects of neuropathic pain, but acute pain sensation is unaffected. This work shows that inflammatory and neuropathic pain have much in common, and suggests that selective blockers of HCN2 may have value as analgesics in the treatment of pain. - Emery EC et al.Trends in Pharmacological Sciences Volume 33, Issue 8, August 2012, Pages 456–463

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