Aberrant somatosensory-evoked responses imply GABAergic dysfunction in Angelman syndrome

Abstract

A role for γ-aminobutyric acid (GABA)ergic inhibition in cortical sensory processing is one of the principle concerns of brain research. Angelman syndrome (AS) is thought to be one of the few neurodevelopmental disorders with GABAergic-related genetic involvement. AS results from a functional deficit of the imprinted UBE3A gene, located at 15q11–q13, resulting mainly from a 4-Mb deletion that includes GABA A receptor subunit genes. These genes are believed to affect the GABAergic system and modulate the clinical severity of AS. To understand the underlying cortical dysfunction, we have investigated the primary somatosensory-evoked responses in AS patients. Subjects included eleven AS patients with a 15q11–q13 deletion (AS Del), two AS patients without a 15q11–q13 deletion, but with a UBE3A mutation (AS non-Del), six epilepsy patients (non-AS) and eleven normal control subjects. Somatosensory-evoked fields (SEFs) in response to median nerve stimulation were measured by magnetoencephalography. The N1m peak latency in AS Del patients was significantly longer (34.6 ± 4.8 ms) than in non-AS patients (19.5 ± 1.2 ms, P < 0.001) or normal control subjects (18.4 ± 1.8 ms, P < 0.001). The next component, P1m, was prolonged and ambiguous and was only detected in patients taking clonazepam. In contrast, SEF waveforms of AS non-Del patients were similar to those of control individuals, rather than to AS Del patients. Thus, GABAergic dysfunction in AS Del patients is likely due to hemizygosity of GABA A receptor subunit genes, suggesting that GABAergic inhibition plays an important role in synchronous activity of human sensory systems.