Reduced GABAergic inhibition explains cortical hyperexcitability in the wobbler mouse model of ALS.
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.
Nieto-Gonzalez
Jose Luis
JL
Synaptic Physiology Laboratory, Department of Physiology and Biophysics, Aarhus University, DK-8000 Aarhus C, Denmark.
Moser
Jakob
J
Lauritzen
Martin
M
Schmitt-John
Thomas
T
Jensen
Kimmo
K
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology*; D051379:Mice; D055369:Miniature Postsynaptic Potentials / Q000502:physiology; D009044:Motor Cortex / Q000378:metabolism / Q000503:physiopathology*; D009433:Neural Inhibition / Q000502:physiology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D009435:Synaptic Transmission / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D005680:gamma-Aminobutyric Acid