Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na
            <sup>+</sup>
            channels

Fleidervish, Ilya A.; Libman, Lior; Katz, Efrat; Gutnick, Michael J.

doi:10.1073/pnas.0803464105

Cited by 77 publications

(40 citation statements)

References 57 publications

(79 reference statements)

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“…Following treatment with 50 nM T3 þ 2.5 mg anti-NT3 þ8 mg anti-FGF2, which reversed the effect of the treatment with anti-NT-3 antibodies, t1 amounted to 0.80 + 0.05 ms and t2 was 8.58 + 2.39 ms (n ¼ 27). Since no statistically significant changes were found, we assume that treatment with these factors does not significantly influence the availability of inactivated Na 1 channels as observed after polyamine withdrawal [7].…”

Section: Results (A) Effects Of Proteins Secreted From Astrocytes (I)mentioning

confidence: 78%

Regulation of neuronal excitability by release of proteins from glial cells

Igelhorst

Niederkinkhaus

Karus

et al. 2015

Phil. Trans. R. Soc. B

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Effects of glial cells on electrical isolation and shaping of synaptic transmission between neurons have been extensively studied. Here we present evidence that the release of proteins from astrocytes as well as microglia may regulate voltage-activated Na þ currents in neurons, thereby increasing excitability and speed of transmission in neurons kept at distance from each other by specialized glial cells. As a first example, we show that basic fibroblast growth factor and neurotrophin-3, which are released from astrocytes by exposure to thyroid hormone, influence each other to enhance Na þ current density in cultured hippocampal neurons. As a second example, we show that the presence of microglia in hippocampal cultures can upregulate Na þ current density. The effect can be boosted by lipopolysaccharides, bacterial membrane-derived stimulators of microglial activation. Comparable effects are induced by the exposure of neuron-enriched hippocampal cultures to tumour necrosis factor-a, which is released from stimulated microglia. Taken together, our findings suggest that release of proteins from various types of glial cells can alter neuronal excitability over a time course of several days. This explains changes in neuronal excitability occurring in states of thyroid hormone imbalance and possibly also in seizures triggered by infectious diseases.

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Section: Results (A) Effects Of Proteins Secreted From Astrocytes (I)mentioning

confidence: 78%

Regulation of neuronal excitability by release of proteins from glial cells

Igelhorst

Niederkinkhaus

Karus

et al. 2015

Phil. Trans. R. Soc. B

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“…Experiments were performed on L5 pyramidal neurons in somatosensory neocortical coronal slices prepared from 2-to 8-wk-old CD-1 mice with the use of techniques that are standard in our laboratory (33). Mice were anesthetized with pentobarbital (60 mg·kg ) and decapitated by using procedures approved by the Institutional Animal Care and Use Committee of Ben-Gurion University.…”

Section: Methodsmentioning

confidence: 99%

Spatial mismatch between the Na ⁺ flux and spike initiation in axon initial segment

Baranauskas

David

Fleidervish

2013

Proc. Natl. Acad. Sci. U.S.A.

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105

163

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It is widely believed that, in cortical pyramidal cells, action potentials (APs) initiate in the distal portion of axon initial segment (AIS) because that is where Na + channel density is highest. To investigate the relationship between the density of Na + channels and the spatiotemporal pattern of AP initiation, we simultaneously recorded Na + flux and action currents along the proximal axonal length. We found that functional Na + channel density is approximately four times lower in the AP trigger zone than in the middle of the AIS, where it is highest. Computational analysis of AP initiation revealed a paradoxical mismatch between the AP threshold and Na + channel density, which could be explained by the lopsided capacitive load imposed on the proximal end of the AIS by the somatodendritic compartment. Favorable conditions for AP initiation are therefore achieved in the distal AIS portion, close to the edge of myelin, where the current source-load ratio is highest. Our findings suggest that cable properties play a central role in determining where the AP starts, such that small plastic changes in the local AIS Na + channel density could have a large influence on neuronal excitability as a whole.neocortex | pyramidal neuron | sodium imaging I n cortical pyramidal cells, as in many CNS neurons, action potentials (APs) generally initiate in the axon initial segment (AIS) (refs. 1-4; reviewed in ref. 5), the proximal part of the axon where the neuronal membrane is not covered with a myelin sheath, and which possesses a distinctive, specialized assembly of voltage-gated channels and associated proteins (6). Because of the pivotal role that the AIS plays in transformation of synaptic input into AP output, precise characterization of its excitable properties is essential for a complete understanding of the cellular mechanisms that underlie operation of cortical neurons and networks. Early theoretical studies proposed two mechanisms to explain preferential AIS AP initiation (7, 8): (i) less current is required to depolarize the AIS membrane to threshold because it is electrically isolated from the neighboring neuronal compartments, and (ii) the depolarizing current density is higher in the AIS than in neighboring compartments, allowing the AIS to overcome their electric load. These two mechanisms are not mutually exclusive, but the technical difficulties that hinder precise measurements in thin neuronal processes have made it difficult to elucidate their relative importance for AP initiation.During the past decade, the isolation hypothesis has been addressed by only a few studies (9), and values of the relevant resistances and capacitances are only approximations. By contrast, the findings by many groups that Na + channel density is relatively high in the proximal axon have focused most attention on the higher current hypothesis, although there remains some controversy as to what extent the density of functional Na + channels is greater in the AIS than in the soma (refs. 10-14; reviewed in ref. 15). The role of high ...

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“…Spermidine itself mediates pro-epileptic effects by increased NO-synthesis in an experimental rat model (Stojanovic et al 2010). Furthermore both spermine and spermidine are potent blockers of voltage-gated Na + channels and their pharmacological depletion leads to increased epileptogenic activity in pyramidal neurons (Fleidervish et al 2008). Modulation of NMDA receptors was further implicated in the etiology of intellectual disability (Igarashi and Kashiwagi 2010;Pegg 2014).…”

Section: N 8 -Acetylspermidine As a Novel Potential Biomarker For Snymentioning

confidence: 99%

N⁸‐acetylspermidine as a potential plasma biomarker for Snyder‐Robinson syndrome identified by clinical metabolomics

Abela

Simmons

Steindl

et al. 2015

J of Inher Metab Disea

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Clinical metabolomics has emerged as a powerful tool to study human metabolism in health and disease. Comparative statistical analysis of untargeted metabolic profiles can reveal perturbations of metabolite levels in diseases and thus has the potential to identify novel biomarkers. Here we have applied a simultaneous genetic-metabolomic approach in twin boys with epileptic encephalopathy of unclear etiology. Clinical exome sequencing identified a novel missense mutation in the spermine synthase gene (SMS) that causes Snyder-Robinson syndrome (SRS). Untargeted plasma metabolome analysis revealed significantly elevated levels of N(8)-acetylspermidine, a precursor derivative of spermine biosynthesis, as a potential novel plasma biomarker for SRS. This result was verified in a third patient with genetically confirmed SRS. This study illustrates the potential of metabolomics as a translational technique to support exome data on a functional and clinical level. Abstract Clinical metabolomics has emerged as a powerful tool to study human metabolism in health and disease. Comparative statistical analysis of untargeted metabolic profiles can reveal perturbations of metabolite levels in diseases and thus has the potential to identify novel biomarkers. Here we have applied a simultaneous genetic-metabolomic approach in twin boys with epileptic encephalopathy of unclear etiology. Clinical exome sequencing identified a novel missense mutation in the spermine synthase gene (SMS) that causes Snyder-Robinson syndrome (SRS). Untargeted plasma metabolome analysis revealed significantly elevated levels of N 8 -acetylspermidine, a precursor derivative of spermine biosynthesis, as a potential novel plasma biomarker for SRS. This result was verified in a third patient with genetically confirmed SRS. This study illustrates the potential of metabolomics as a translational technique to support exome data on a functional and clinical level.

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Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na ⁺ channels

Cited by 77 publications

References 57 publications

Regulation of neuronal excitability by release of proteins from glial cells

Regulation of neuronal excitability by release of proteins from glial cells

Spatial mismatch between the Na ⁺ flux and spike initiation in axon initial segment

N⁸‐acetylspermidine as a potential plasma biomarker for Snyder‐Robinson syndrome identified by clinical metabolomics

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Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na + channels

Cited by 77 publications

References 57 publications

Regulation of neuronal excitability by release of proteins from glial cells

Regulation of neuronal excitability by release of proteins from glial cells

Spatial mismatch between the Na + flux and spike initiation in axon initial segment

N8‐acetylspermidine as a potential plasma biomarker for Snyder‐Robinson syndrome identified by clinical metabolomics

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Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na ⁺ channels

Spatial mismatch between the Na ⁺ flux and spike initiation in axon initial segment

N⁸‐acetylspermidine as a potential plasma biomarker for Snyder‐Robinson syndrome identified by clinical metabolomics