Molecular Autism (Jul 2019)

Mechanisms underlying the EEG biomarker in Dup15q syndrome

  • Joel Frohlich,
  • Lawrence T. Reiter,
  • Vidya Saravanapandian,
  • Charlotte DiStefano,
  • Scott Huberty,
  • Carly Hyde,
  • Stormy Chamberlain,
  • Carrie E. Bearden,
  • Peyman Golshani,
  • Andrei Irimia,
  • Richard W. Olsen,
  • Joerg F. Hipp,
  • Shafali S. Jeste

DOI
https://doi.org/10.1186/s13229-019-0280-6
Journal volume & issue
Vol. 10, no. 1
pp. 1 – 15

Abstract

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Abstract Background Duplications of 15q11.2-q13.1 (Dup15q syndrome), including the paternally imprinted gene UBE3A and three nonimprinted gamma-aminobutyric acid type-A (GABAA) receptor genes, are highly penetrant for neurodevelopmental disorders such as autism spectrum disorder (ASD). To guide targeted treatments of Dup15q syndrome and other forms of ASD, biomarkers are needed that reflect molecular mechanisms of pathology. We recently described a beta EEG phenotype of Dup15q syndrome, but it remains unknown which specific genes drive this phenotype. Methods To test the hypothesis that UBE3A overexpression is not necessary for the beta EEG phenotype, we compared EEG from a reference cohort of children with Dup15q syndrome (n = 27) to (1) the pharmacological effects of the GABAA modulator midazolam (n = 12) on EEG from healthy adults, (2) EEG from typically developing (TD) children (n = 14), and (3) EEG from two children with duplications of paternal 15q (i.e., the UBE3A-silenced allele). Results Peak beta power was significantly increased in the reference cohort relative to TD controls. Midazolam administration recapitulated the beta EEG phenotype in healthy adults with a similar peak frequency in central channels (f = 23.0 Hz) as Dup15q syndrome (f = 23.1 Hz). Both paternal Dup15q syndrome cases displayed beta power comparable to the reference cohort. Conclusions Our results suggest a critical role for GABAergic transmission in the Dup15q syndrome beta EEG phenotype, which cannot be explained by UBE3A dysfunction alone. If this mechanism is confirmed, the phenotype may be used as a marker of GABAergic pathology in clinical trials for Dup15q syndrome.

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