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Reduced GABAergic inhibition explains cortical hyperexcitability in the wobbler mouse model of ALS

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  • Jose Luis Nieto-Gonzalez
  • Jakob Moser
  • Martin Lauritzen
  • Thomas Schmitt-John
  • Kimmo Jensen
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Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of the central nervous system. Symptomatic and presymptomatic ALS patients demonstrate cortical hyperexcitability, which raises the possibility that alterations in inhibitory gamma-aminobutyric acid (GABA)ergic system could underlie this dysfunction. Here, we studied the GABAergic system in cortex using patch-clamp recordings in the wobbler mouse, a model of ALS. In layer 5 pyramidal neurons of motor cortex, the frequency of GABA(A) receptor-mediated spontaneous inhibitory postsynaptic currents was reduced by 72% in wobbler mice. Also, miniature inhibitory postsynaptic currents recorded under blockade of action potentials were decreased by 64%. Tonic inhibition mediated by extrasynaptic GABA(A) receptors was reduced by 87%. In agreement, we found a decreased density of parvalbumin- and somatostatin-positive inhibitory interneurons and reduced vesicular GABA transporter immunoreactivity in the neuropil. Finally, we observed an increased input resistance and excitability of wobbler excitatory neurons, which could be explained by lack of GABA(A) receptor-mediated influences. In conclusion, we demonstrate decreases in GABAergic inhibition, which might explain the cortical hyperexcitability in wobbler mice.
OriginalsprogEngelsk
TidsskriftCerebral Cortex
Vol/bind21
Udgave nummer3
Sider (fra-til)625-35
Antal sider11
ISSN1047-3211
DOI
StatusUdgivet - 1 mar. 2011

ID: 32310378