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Target Concepts:
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Query: UMLS:C0002736 (
amyotrophic lateral sclerosis
)
19,048
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Cortical hyperexcitability is an early and intrinsic feature of
Amyotrophic Lateral Sclerosis
(
ALS
), but the mechanisms underlying this critical neuronal dysfunction are poorly understood. Recently, we have demonstrated that layer V pyramidal neurons (PNs) in the primary motor cortex (M1) of one-month old (P30) G93A
ALS
mice display an early hyperexcitability status compared to Control mice. In order to investigate the time-dependent evolution of the cortical excitability in the G93A
ALS
model, here we have performed an electrophysiological and immunohistochemical study at three different mouse ages. M1 PNs from 14-days old (P14) G93A mice have shown no excitability alterations, while M1 PNs from 3-months old (P90) G93A mice have shown a hypoexcitability status, compared to Control mice. These age-dependent cortical excitability dysfunctions correlate with a similar time-dependent trend of the persistent sodium current (
INa
P
) amplitude alterations, suggesting that
INa
P
may play a crucial role in the G93A cortical excitability aberrations. Specifically, immunohistochemistry experiments have indicated that the expression level of the NaV1.6 channel, one of the voltage-gated Na
+
channels mainly distributed within the central nervous system, varies in G93A primary motor cortex during disease progression, according to the excitability and
INa
P
alterations, but not in other cortical areas. Microfluorometry experiments, combined with electrophysiological recordings, have verified that P30 G93A PNs hyperexcitability is associated to a greater accumulation of intracellular calcium ([Ca
2+
]
i
) compared to Control PNs, and that this difference is still present when G93A and Control PNs fire action potentials at the same frequency. These results suggest that [Ca
2+
]
i
de-regulation in G93A PNs may contribute to neuronal demise and that the NaV1.6 channels could be a potential therapeutic target to ameliorate
ALS
disease progression.
...
PMID:Modified age-dependent expression of NaV1.6 in an ALS model correlates with motor cortex excitability alterations. 3130 44
