The PDE10A Inhibitor TAK-063 Reverses Sound-Evoked EEG Abnormalities in a Mouse Model of Fragile X Syndrome

A Correction to this article was published on 30 March 2021

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Abstract

Fragile X syndrome (FXS) is a genetic neurodevelopmental syndrome characterized by increased anxiety, repetitive behaviors, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we have identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. In this study, we test a specific candidate mechanism for engagement of multielectrode array (MEA) EEG biomarkers in the FXS mouse model. We administered TAK-063, a potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor, to Fmr1 KO mice, and examined its effects on MEA EEG biomarkers. We demonstrate significant dose-related amelioration of inter-trial phase coherence (ITPC) to temporally modulated auditory stimuli by TAK-063 in Fmr1 KO mice. Our data suggest that TAK-063 improves cortical auditory stimulus processing in Fmr1 KO mice, without significantly depressing baseline EEG power or causing any noticeable sedation or behavioral side effects. Thus, the PDE10A inhibitor TAK-063 has salutary effects on normalizing EEG biomarkers in a mouse model of FXS and should be pursued in further translational treatment development.

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Change history

Abbreviations

EEG:

Electroencephalography

FMRP:

Fragile X mental retardation protein

FXS:

Fragile X syndrome

LC/MS/MS:

Liquid chromatography/tandem mass spectrometry

ITPC:

Inter-trial phase coherence (phase locking factor)

K/X:

Ketamine/xylazine

MEA:

Multielectrode array

PDE:

Phosphodiesterase

PK:

Pharmacokinetics

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Acknowledgments

We acknowledge members of the Binder laboratory and Drs. Daniel Curran and Tauhid Ali from Takeda International for fruitful discussions. This work was supported by the Takeda International–UK, Rare Diseases Therapeutic Area Unit.

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Correspondence to Devin K. Binder.

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The original online version of this article was revised to add a note stating Manbir S. Sandhu and Samantha A. Assad are co-second authors.

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Jonak, C.R., Sandhu, M.S., Assad, S.A. et al. The PDE10A Inhibitor TAK-063 Reverses Sound-Evoked EEG Abnormalities in a Mouse Model of Fragile X Syndrome. Neurotherapeutics (2021). https://doi.org/10.1007/s13311-021-01005-w

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Key Words

  • Fragile X syndrome
  • electroencephalography
  • biomarker
  • TAK-063
  • phosphodiesterase