Amyotrophic lateral sclerosis (ALS) is a devastating form of adult onset motor neuron degeneration that affects multiple areas of the central nervous system. Recent studies have suggested a cortical hyperexcitability in presymptomatic ALS patients, raising the possibility that a decrease in inhibitory GABAergic systems could underlie this dysfunction. Here, we studied GABAergic inhibition in frontal cortex using patch-clamp recordings and immunohistochemistry in the wobbler mouse, a model of ALS. Layer 5 pyramidal neurons were identified by their typical shape under infrared video microscopy and post hoc by intracellular labeling. Whole-cell recordings showed that the frequency of GABAA 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 GABAA receptors was reduced by 87%. Pyramidal neurons in wobbler mice displayed an increased input resistance and excitability, which could be explained by the lack of GABAA receptor mediated influences. Finally, immunohistochemical experiments were carried out to examine the density of parvalbumin and somatostatin-positive interneurons, and of VGAT-positive synaptic (GABAergic) boutons. In wobbler mice, this revealed a decrease in the density of parvalbumin (by 27%) and somatostatin (by 37%), while the optical density in the neuropil of VGAT-positive boutons was decreased by 35%. In conclusion, we provide evidence suggesting that a decrease in GABAergic inhibition underlies cortical hyperexcitability in wobbler mice.