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Neuroscience: CNS disease, pain, brain research, ion channels, synaptic transmission, channelopathies, neuronal network
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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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Presynaptic NMDA Receptor Mechanisms for Enhancing Spontaneous Neurotransmitter Release

NMDA receptors (NMDARs) are required for experience-driven plasticity during formative periods of brain development and are critical for neurotransmission throughout postnatal life. Most NMDAR functions have been ascribed to postsynaptic sites of action, but there is now an appreciation that presynaptic NMDARs (preNMDARs) can modulate neurotransmitter release in many brain regions, including the neocortex. Despite these advances, the cellular mechanisms by which preNMDARs can affect neurotransmitter release are largely unknown. Here we interrogated preNMDAR functions pharmacologically to determine how these receptors promote spontaneous neurotransmitter release in mouse primary visual cortex. Our results provide three new insights into the mechanisms by which preNMDARs can function. First, preNMDARs can enhance spontaneous neurotransmitter release tonically with minimal extracellular Ca2+ or with major sources of intracellular Ca2+blocked. Second, lowering extracellular Na+ levels reduces the contribution of preNMDARs to spontaneous transmitter release significantly. Third, preNMDAR enhance transmitter release in part through protein kinase C signaling. These data demonstrate that preNMDARs can act through novel pathways to promote neurotransmitter release in the absence of action potentials. - by Kunz PA et al., The Journal of Neuroscience, 1 May 2013, 33(18)

Julien Hering, PhD's insight:

Nice study about spontaneous activity at the synapses by NMDA receptors

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Ion channels in genetic and acquired forms of epilepsy

Ion channels in genetic and acquired forms of epilepsy | Neuroscience_topics | Scoop.it

Genetic mutations causing dysfunction of both voltage- and ligand-gated ion channels make a major contribution to the cause of many different types of familial epilepsy. Key mechanisms comprise defective Na+ channels of inhibitory neurons, or GABAA receptors affecting pre- or postsynaptic GABAergic inhibition, or a dysfunction of different types of channels at axon initial segments. Many of these ion channel mutations have been modelled in mice, which has largely contributed to the understanding of where and how the ion channel defects lead to neuronal hyperexcitability. Animal models of febrile seizures or mesial temporal epilepsy have shown that dendritic K+ channels, hyperpolarization-activated cation channels and T-type Ca2+ channels play important roles in the generation of seizures. For the latter, it has been shown that suppression of their function by pharmacological mechanisms or in knock-out mice can antagonize epileptogenesis. Defects of ion channel function are also associated with forms of acquired epilepsy. Autoantibodies directed against ion channels or associated proteins, such as K+ channels, LGI1 or NMDA receptors, have been identified in epileptic disorders that can largely be included under the term limbic encephalitis which includes limbic seizures, status epilepticus and psychiatric symptoms. We conclude that ion channels and associated proteins are important players in different types of genetic and acquired epilepsies. Nevertheless, the molecular bases for most common forms of epilepsy are not yet clear, and evidence to be discussed indicates just how much more we need to understand about the complex mechanisms that underlie epileptogenesis. - Lerche H et al.The Journal of Physiology, 591, 753-764., February 15, 2013

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Janys Venne's curator insight, October 26, 2013 2:02 AM


I'll appreciate your time & help to visit my website on #seizures #epilepsy at http://seizures.dolyan.com/. Thank you :)

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Ion channels in genetic and acquired forms of epilepsy

Ion channels in genetic and acquired forms of epilepsy | Neuroscience_topics | Scoop.it
[Abstract] Genetic mutations causing dysfunction of both voltage- and ligand-gated ion channels make a major contribution to the cause of many different types of familial epilepsy. Key mechanisms comprise defective Na+ channels of inhibitory neurons or GABAA receptors affecting pre- or postsynaptic GABAergic inhibition, or a dysfunction of different types of channels at axon initial segments. Many of the mentioned ion channel mutations have been modelled in mice which has largely contributed to the understanding of where and how the ion channel defects lead to neuronal hyperexcitability. Defects of ion channel function are also associated with forms of acquired epilepsies. Animal models of febrile seizures or mesial temporal epilepsy have shown that dendritic K+ channels, hyperpolarization-activated cation channels and T-type Ca2+ channels play important roles in the generation of seizures. For the latter, it has been shown that suppression of their function by pharmacological mechanisms or in knock-out mice can antagonize epileptogenesis. Autoantibodies directed against ion channels or associated proteins, such as K+ channels, LGI1 or NMDA receptors, have been identified in epileptic disorders which are summarized under the term limbic encephalitis comprising limbic seizures, status epilepticus and psychiatric symptoms. We conclude that ion channels and associated proteins are important players for different types of genetic and acquired epilepsies. Nevertheless, the molecular bases for most common forms of epilepsy are not yet clear, and evidence to be discussed indicates just how much more we need to understand about the complex mechanisms that underlie epileptogenesis. - Lerche H et al., The Journal of Physiology, doi:
10.1113/jphysiol.2012.240606
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Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons

Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons | Neuroscience_topics | Scoop.it

Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer's disease pathophysiology. Cellular prion protein (PrPC) selectively binds oligomeric Aβ and can mediate Alzheimer's disease–related phenotypes. We examined the specificity, distribution and signaling of Aβ-PrPC complexes, seeking to understand how they might alter the function of NMDA receptors (NMDARs) in neurons. PrPC is enriched in postsynaptic densities, and Aβ-PrPC interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from the brains of individuals with Alzheimer's disease interacted with PrPC to activate Fyn. Aβ engagement of PrPC-Fyn signaling yielded phosphorylation of the NR2B subunit of NMDARs, which was coupled to an initial increase and then a loss of surface NMDARs. Aβ-induced dendritic spine loss and lactate dehydrogenase release required both PrPC and Fyn, and human familial Alzheimer's disease transgene–induced convulsive seizures did not occur in mice lacking PrPC. These results delineate an Aβ oligomer signal transduction pathway that requires PrPC and Fyn to alter synaptic function, with deleterious consequences in Alzheimer's disease. - Um JW et al.Nature Neuroscience 15, 1227–1235, 22 July 2012

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NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease

NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease | Neuroscience_topics | Scoop.it

NMDA receptors (NMDARs) are glutamate-gated ion channels and are crucial for neuronal communication. NMDARs form tetrameric complexes that consist of several homologous subunits. The subunit composition of NMDARs is plastic, resulting in a large number of receptor subtypes. As each receptor subtype has distinct biophysical, pharmacological and signalling properties, there is great interest in determining whether individual subtypes carry out specific functions in the CNS in both normal and pathological conditions. Here, we review the effects of subunit composition on NMDAR properties, synaptic plasticity and cellular mechanisms implicated in neuropsychiatric disorders. Understanding the rules and roles of NMDAR diversity could provide new therapeutic strategies against dysfunctions of glutamatergic transmission - by Pierre PaolettiCamilla Bellone Qiang Zhou, Nature Reviews Neuroscience 14, 383–400 (2013)

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Metabotropic NMDA receptor function is required for β-amyloid–induced synaptic depression

The mechanisms by which β-amyloid (Aβ), a peptide fragment believed to contribute to Alzheimer’s disease, leads to synaptic deficits are not known. Here we find that elevated oligomeric Aβ requires ion flux-independent function of NMDA receptors (NMDARs) to produce synaptic depression. Aβ activates this metabotropic NMDAR function on GluN2B-containing NMDARs but not on those containing GluN2A. Furthermore, oligomeric Aβ leads to a selective loss of synaptic GluN2B responses, effecting a switch in subunit composition from GluN2B to GluN2A, a process normally observed during development. Our results suggest that conformational changes of the NMDAR, and not ion flow through its channel, are required for Aβ to produce synaptic depression and a switch in NMDAR composition. This Aβ-induced signaling mediated by alterations in GluN2B conformation may be a target for therapeutic intervention of Alzheimer’s disease. (...) - by Kessels HW et al.PNASMarch 5, 2013 vol. 110 no. 104033-4038

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NMDA and GABAB (KIR) Conductances: The “Perfect Couple” for Bistability

[Abstract] Networks that produce persistent firing in response to novel input patterns are thought to be important in working memory and other information storage functions. One possible mechanism for maintaining persistent firing is dendritic voltage bistability in which the depolarized state depends on the voltage dependence of the NMDA conductance at recurrent synapses. In previous models, the hyperpolarized state is dependent on voltage-independent conductances, including GABAA. The interplay of these conductances leads to bistability, but its robustness is limited by the fact that the conductance ratio must be within a narrow range. The GABAB component of inhibitory transmission was not considered in previous analyses. Here, we show that the voltage dependence of the inwardly rectifying potassium (KIR) conductance activated by GABAB receptors adds substantial robustness to network simulations of bistability and the persistent firing that it underlies. The hyperpolarized state is robust because, at hyperpolarized potentials, the GABAB/KIR conductance is high and the NMDA conductance is low; the depolarized state is robust because, at depolarized potentials, the NMDA conductance is high and the GABAB/KIR conductance is low. Our results suggest that this complementary voltage dependence of GABAB/KIR and NMDA conductances makes them a “perfect couple” for producing voltage bistability. - Sanders H. et al., The Journal of Neuroscience, 9 January 2013, 33(2): 424-429

Julien Hering, PhD's insight:

The NMDA/GABAB receptor channels bipolar couple is perfect to generate bistability in a narrow window of voltage. 

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Synaptic Dysfunction in Depression: Potential Therapeutic Targets

[Review] Basic and clinical studies demonstrate that depression is associated with reduced size of brain regions that regulate mood and cognition, including the prefrontal cortex and the hippocampus, and decreased neuronal synapses in these areas. Antidepressants can block or reverse these neuronal deficits, although typical antidepressants have limited efficacy and delayed response times of weeks to months. A notable recent discovery shows that ketamine, a N-methyl-D-aspartate receptor antagonist, produces rapid (within hours) antidepressant responses in patients who are resistant to typical antidepressants. Basic studies show that ketamine rapidly induces synaptogenesis and reverses the synaptic deficits caused by chronic stress. These findings highlight the central importance of homeostatic control of mood circuit connections and form the basis of a synaptogenic hypothesis of depression and treatment response. by Dunam RS & Aghajanian GKScience 5 October 2012: Vol. 338 no. 6103 pp. 68-72

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Dissecting spatial knowledge from spatial choice by hippocampal NMDA receptor deletion

Dissecting spatial knowledge from spatial choice by hippocampal NMDA receptor deletion | Neuroscience_topics | Scoop.it

Hippocampal NMDA receptors (NMDARs) and NMDAR-dependent synaptic plasticity are widely considered crucial substrates of long-term spatial memory, although their precise role remains uncertain. Here we show that Grin1ΔDGCA1 mice, lacking GluN1 and hence NMDARs in all dentate gyrus and dorsal CA1 principal cells, acquired the spatial reference memory water maze task as well as controls, despite impairments on the spatial reference memory radial maze task. When we ran a spatial discrimination water maze task using two visually identical beacons, Grin1ΔDGCA1 mice were impaired at using spatial information to inhibit selecting the decoy beacon, despite knowing the platform's actual spatial location. This failure could suffice to impair radial maze performance despite spatial memory itself being normal. Thus, these hippocampal NMDARs are not essential for encoding or storing long-term, associative spatial memories. Instead, we demonstrate an important function of the hippocampus in using spatial knowledge to select between alternative responses that arise from competing or overlapping memories. - Bannerman DM et al., Nature Neuroscience 15, 1153–1159 (2012) - http://www.nature.com/neuro/journal/v15/n8/full/nn.3166.html

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