Cortical hyperexcitability has been observed in Amyotrophic Lateral Sclerosis (ALS) patients. Familial ALS accounts for 10% of all cases and mutations of the Cu,Zn superoxide dismutase (SOD1) gene have been identified in about 20% of the familial cases. The aim of this study was to investigate whether in a mouse model of ALS the cortical neurons developed hyperexcitability due to intrinsic properties of the single cell. We first examined the passive membrane properties and the pattern of repetitive firing in cultured cortical neurons from Control mice and transgenic mice expressing high levels of the human mutated protein (Gly(93)-Ala, G93A). The former did not display significantly differing values between Control and C93A cortical neurons. However, the threshold potential and time of the first action potential decreased significantly and the firing frequency increased significantly in the G93A compared to Control neurons. The analysis of the voltage-dependent sodium currents revealed that the fast transient sodium current was unaffected by the SOD1 mutation whereas the persistent sodium current was significantly higher in the mutated neurons. Finally, Riluzole, a selective blocker of the persistent sodium current at low concentrations, decreased the firing frequency in G93A neurons, strongly indicating an involvement of this current in the observed hyperexcitabiliry. These are the first data that demonstrate an intrinsic hyperexcitability in the C93A Cortical neurons due to a higher current density of the persistent sodium current in the mutated neurons and open up new prospects of understanding ALS disease etiopathology. (c) 2008 Elsevier Inc. All rights reserved.

Pieri, M., Carunchio, I., Curcio, L., Mercuri, N.B., & Zona, C. (2009). Increased persistent sodium current determines cortical hyperexcitability in a genetic model of amyotrophic lateral sclerosis. EXPERIMENTAL NEUROLOGY, 215(2), 368-379 [10.1016/j.expneurol.2008.11.002].

Increased persistent sodium current determines cortical hyperexcitability in a genetic model of amyotrophic lateral sclerosis

PIERI, MASSIMO;MERCURI, NICOLA BIAGIO;ZONA, CRISTINA
2009

Abstract

Cortical hyperexcitability has been observed in Amyotrophic Lateral Sclerosis (ALS) patients. Familial ALS accounts for 10% of all cases and mutations of the Cu,Zn superoxide dismutase (SOD1) gene have been identified in about 20% of the familial cases. The aim of this study was to investigate whether in a mouse model of ALS the cortical neurons developed hyperexcitability due to intrinsic properties of the single cell. We first examined the passive membrane properties and the pattern of repetitive firing in cultured cortical neurons from Control mice and transgenic mice expressing high levels of the human mutated protein (Gly(93)-Ala, G93A). The former did not display significantly differing values between Control and C93A cortical neurons. However, the threshold potential and time of the first action potential decreased significantly and the firing frequency increased significantly in the G93A compared to Control neurons. The analysis of the voltage-dependent sodium currents revealed that the fast transient sodium current was unaffected by the SOD1 mutation whereas the persistent sodium current was significantly higher in the mutated neurons. Finally, Riluzole, a selective blocker of the persistent sodium current at low concentrations, decreased the firing frequency in G93A neurons, strongly indicating an involvement of this current in the observed hyperexcitabiliry. These are the first data that demonstrate an intrinsic hyperexcitability in the C93A Cortical neurons due to a higher current density of the persistent sodium current in the mutated neurons and open up new prospects of understanding ALS disease etiopathology. (c) 2008 Elsevier Inc. All rights reserved.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/09
English
Con Impact Factor ISI
ALS; Ionic channels; Patch-clamp; Persistent sodium current; Riluzole
Pieri, M., Carunchio, I., Curcio, L., Mercuri, N.B., & Zona, C. (2009). Increased persistent sodium current determines cortical hyperexcitability in a genetic model of amyotrophic lateral sclerosis. EXPERIMENTAL NEUROLOGY, 215(2), 368-379 [10.1016/j.expneurol.2008.11.002].
Pieri, M; Carunchio, I; Curcio, L; Mercuri, Nb; Zona, C
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/45153
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