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

Neurotherapeutics (2021)Cite this article

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

References

  1. 1.

    Crawford DC, Acuña JM, Sherman SL. FMR1 and the fragile X syndrome: Human genome epidemiology review. Genet Med, 3, 359-371 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Yu S, Pritchard M, Kremer E et al. Fragile X genotype characterized by an unstable region of DNA. Science, 252, 1179-1181 (1991).

    CAS  Google Scholar 

  3. 3.

    Darnell Jennifer C, Van Driesche Sarah J, Zhang C et al. FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism. Cell, 146, 247-261 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Abbeduto L, Hagerman RJ. Language and communication in fragile X syndrome. Ment Retard Dev Disabil Res Rev, 3, 313-322 (1997).

    Google Scholar 

  5. 5.

    Berry-Kravis E. Epilepsy in fragile X syndrome. Dev Med Child Neurol, 44, 724-728 (2002).

    Google Scholar 

  6. 6.

    Hagerman RJ, Berry-Kravis E, Kaufmann WE et al. Advances in the treatment of fragile X syndrome. Pediatrics, 123, 378-390 (2009).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Miller LJ, McIntosh DN, McGrath J et al. Electrodermal responses to sensory stimuli in individuals with fragile X syndrome: A preliminary report. Am J Med Genet, 83, 268-279 (1999).

    CAS  Google Scholar 

  8. 8.

    Musumeci SA, Hagerman RJ, Ferri R et al. Epilepsy and EEG Findings in Males with Fragile X Syndrome. Epilepsia, 40, 1092-1099 (1999).

    CAS  Google Scholar 

  9. 9.

    Roberts JE, Hatton DD, Bailey DB. Development and Behavior of Male Toddlers With Fragile X Syndrome. J Early Interv, 24, 207-223 (2001).

    Google Scholar 

  10. 10.

    Sabaratnam M, Vroegop PG, Gangadharan SK. Epilepsy and EEG findings in 18 males with fragile X syndrome. Seizure, 10, 60-63 (2001).

    CAS  Google Scholar 

  11. 11.

    Sinclair D, Oranje B, Razak KA, Siegel SJ, Schmid S. Sensory processing in autism spectrum disorders and Fragile X syndrome-From the clinic to animal models. Neurosci Biobehav Rev, 76(Pt B), 235-253 (2017).

    CAS  Google Scholar 

  12. 12.

    Van der Molen MJW, Huizinga M, Huizenga HM et al. Profiling Fragile X Syndrome in males: Strengths and weaknesses in cognitive abilities. Res Dev Disabil, 31, 426-439 (2010).

    Google Scholar 

  13. 13.

    Wisniewski KE, Segan SM, Miezejeski CM, Sersen EA, Rudelli RD. The fra(X) syndrome: Neurological, electrophysiological, and neuropathological abnormalities. Am J Med Genet, 38, 476-480 (1991).

    CAS  Google Scholar 

  14. 14.

    Castrén M, Paakkonen A, Tarkka IM, Ryynanen M, Partanen J. Augmentation of auditory N1 in children with fragile X syndrome. Brain Topogr, 15(3), 165-171 (2003).

    Google Scholar 

  15. 15.

    Schneider A, Leigh MJ, Adams P et al. Electrocortical changes associated with minocycline treatment in fragile X syndrome. J Psychopharmacol, 27(10), 956-963 (2013).

    CAS  Google Scholar 

  16. 16.

    Berry-Kravis EM, Lindemann L, Jønch AE et al. Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome. Nat Rev Drug Discov, 17, 280-299 (2018).

    CAS  Google Scholar 

  17. 17.

    Jonak CR, Lovelace JW, Ethell IM, Razak KA, Binder DK. Reusable Multielectrode Array Technique for Electroencephalography in Awake Freely Moving Mice. Front Integr Neurosci, 12, 53 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Jonak CR, Lovelace JW, Ethell IM, Razak KA, Binder DK. Multielectrode array analysis of EEG biomarkers in a mouse model of Fragile X Syndrome. Neurobiol Dis, 138, 104794 (2020).

    CAS  Google Scholar 

  19. 19.

    Ethridge LE, White SP, Mosconi MW et al. Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome. Mol Autism, 8, 22 (2017).

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Kunitomo J, Yoshikawa M, Fushimi M et al. Discovery of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyri dazin-4(1H)-one (TAK-063), a highly potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor. J Med Chem, 57(22), 9627-9643 (2014).

    CAS  Google Scholar 

  21. 21.

    Suzuki K, Harada A, Shiraishi E, Kimura H. In vivo pharmacological characterization of TAK-063, a potent and selective phosphodiesterase 10A inhibitor with antipsychotic-like activity in rodents. J Pharmacol Exp Ther, 352(3), 471-479 (2015).

    CAS  Google Scholar 

  22. 22.

    Macek TA, McCue M, Dong X et al. A phase 2, randomized, placebo-controlled study of the efficacy and safety of TAK-063 in subjects with an acute exacerbation of schizophrenia. Schizophr Res, 204, 289-294 (2019).

    Google Scholar 

  23. 23.

    Shiraishi E, Suzuki K, Harada A, Suzuki N, Kimura H. The Phosphodiesterase 10A Selective Inhibitor TAK-063 Improves Cognitive Functions Associated with Schizophrenia in Rodent Models. J Pharmacol Exp Ther, 356(3), 587-595 (2016).

    Google Scholar 

  24. 24.

    Suzuki K, Harada A, Suzuki H, Miyamoto M, Kimura H. TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms. Neuropsychopharmacology, 41(9), 2252-2262 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Suzuki K, Kimura H. TAK-063, a novel PDE10A inhibitor with balanced activation of direct and indirect pathways, provides a unique opportunity for the treatment of schizophrenia. CNS Neurosci Ther, 24(7), 604-614 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Harada A, Suzuki K, Kimura H. TAK-063, a Novel Phosphodiesterase 10A Inhibitor, Protects from Striatal Neurodegeneration and Ameliorates Behavioral Deficits in the R6/2 Mouse Model of Huntington's Disease. J Pharmacol Exp Ther, 360(1), 75-83 (2017).

    CAS  Google Scholar 

  27. 27.

    Berry-Kravis E, Hicar M, Ciurlionis R. Reduced cyclic AMP production in fragile X syndrome: cytogenetic and molecular correlations. Pediatr Res, 38(5), 638-643 (1995).

    CAS  Google Scholar 

  28. 28.

    Berry-Kravis E, Huttenlocher PR. Cyclic AMP metabolism in fragile X syndrome. Ann Neurol, 31(1), 22-26 (1992).

    CAS  Google Scholar 

  29. 29.

    Maurin T, Melancia F, Jarjat M et al. Involvement of Phosphodiesterase 2A Activity in the Pathophysiology of Fragile X Syndrome. Cereb Cortex, 29(8), 3241-3252 (2019).

    Google Scholar 

  30. 30.

    Choi CH, Schoenfeld BP, Weisz ED et al. PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome. J Neurosci, 35(1), 396-408 (2015).

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Gurney ME, Cogram P, Deacon RM, Rex C, Tranfaglia M. Multiple Behavior Phenotypes of the Fragile-X Syndrome Mouse Model Respond to Chronic Inhibition of Phosphodiesterase-4D (PDE4D). Sci Rep, 7(1), 14653 (2017).

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Bakker CE, Verheij C et al. Fmr1 knockout mice: a model to study fragile X mental retardation. The Dutch-Belgian Fragile X Consortium. Cell, 78(1), 23-33 (1994).

    Google Scholar 

  33. 33.

    Artieda J, Valencia M, Alegre M, Olaziregi O, Urrestarazu E, Iriarte J. Potentials evoked by chirp-modulated tones: A new technique to evaluate oscillatory activity in the auditory pathway. Clin Neurophysiol, 115, 699-709 (2004).

    CAS  Google Scholar 

  34. 34.

    Pérez-Alcázar M, Nicolás MJJ, Valencia M, Alegre M, Iriarte J, Artieda J. Chirp-evoked potentials in the awake and anesthetized rat. A procedure to assess changes in cortical oscillatory activityExp Neurol, 210, 144-153 (2008).

    Google Scholar 

  35. 35.

    Purcell DW, John SM, Schneider BA, Picton TW. Human temporal auditory acuity as assessed by envelope following responses. J Acoust Soc Am, 116, 3581-3593 (2004).

    Google Scholar 

  36. 36.

    Tallon-Baudry C, Bertrand O, Delpuech C, Pernier J. Stimulus specificity of phase-locked and non-phase-locked 40 Hz visual responses in human. J Neurosci, 16, 4240-4249 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Maris E, Oostenveld R. Nonparametric statistical testing of EEG- and MEG-data. J Neurosci Methods, 164(1), 177-190 (2007).

    Google Scholar 

  38. 38.

    Berry-Kravis E, Sklena P. Demonstration of abnormal cyclic AMP production in platelets from patients with fragile X syndrome. Am J Med Genet, 45(1), 81-87 (1993).

    CAS  Google Scholar 

  39. 39.

    Tsai M, Chrones L, Xie J, Gevorkyan H, Macek TA. A phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-063, a selective PDE10A inhibitor. Psychopharmacology, 233(21-22), 3787-3795 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Sinclair D, Featherstone R, Naschek M et al. GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Behavioral Deficits in the Fmr1 Knockout Mouse Model of Fragile X Syndrome. Eneuro, 4, ENEURO.0380-0316.2017 (2017).

    Google Scholar 

  41. 41.

    Ethridge LE, De Stefano LA, Schmitt LM et al. Auditory EEG Biomarkers in Fragile X Syndrome: Clinical Relevance. Front Integr Neurosci, 13, 60 (2019).

    PubMed  PubMed Central  Google Scholar 

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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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Affiliations

  1. Division of Biomedical Sciences, School of Medicine, University of California, 900 University Avenue, Riverside, CA, 92521, USA

    Carrie R. Jonak, Manbir S. Sandhu, Samantha A. Assad, Jacqueline A. Barbosa & Devin K. Binder

  2. Takeda International – UK, Rare Diseases Therapeutic Area Unit, 1 Kingdom Street, London, W2 6BD, UK

    Mahindra Makhija

  3. Neuroscience Graduate Program, University of California, Riverside, CA, USA

    Devin K. Binder

Authors
  1. Carrie R. Jonak
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  2. Manbir S. Sandhu
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  3. Samantha A. Assad
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  4. Jacqueline A. Barbosa
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  5. Mahindra Makhija
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  6. Devin K. Binder
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Correspondence to Devin K. Binder.

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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