2. Academic Validation
  3. Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington's Disease Models

Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington's Disease Models

  • Neuron. 2016 Dec 21;92(6):1220-1237. doi: 10.1016/j.neuron.2016.10.064.
Vahri Beaumont 1,  Sheng Zhong 2,  Hai Lin 2,  WenJin Xu 2,  Amyaouch Bradaia 3,  Esther Steidl 3,  Melanie Gleyzes 3,  Kristian Wadel 3,  Bruno Buisson 3,  Fernando E Padovan-Neto 4,  Shreaya Chakroborty 4,  Karen M Ward 5,  John F Harms 5,  Jose Beltran 2,  Mei Kwan 2,  Afshin Ghavami 2,  Jenny Häggkvist 6,  Miklós Tóth 6,  Christer Halldin 6,  Andrea Varrone 6,  Christoph Schaab 7,  J Nikolaj Dybowski 7,  Sarah Elschenbroich 7,  Kimmo Lehtimäki 8,  Taneli Heikkinen 8,  Larry Park 9,  James Rosinski 9,  Ladislav Mrzljak 9,  Daniel Lavery 9,  Anthony R West 4,  Christopher J Schmidt 5,  Margaret M Zaleska 5,  Ignacio Munoz-Sanjuan 9
Affiliations

Affiliations

  • 1 CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, CA 90045, USA. Electronic address: [email protected].
  • 2 Psychogenics Inc., 100 Philips Parkway, Montvale, NJ 07645, USA.
  • 3 Neuroservice, Domaine Saint Hilaire, CS30531, 595 rue Pierre BERTHIER, 13593 Aix-en-Provence Cedex 3, France.
  • 4 Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA.
  • 5 Neuroscience Research Unit, Pfizer, Inc., 610 Main Street, Cambridge, MA 02139, USA.
  • 6 Department of Clinical Neuroscience, Karolinska Institutet, Centre for Psychiatry Research, R5:02, Karolinska University Hospital, 17176 Stockholm, Sweden.
  • 7 Evotec (München) GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany.
  • 8 Charles River Discovery, Microkatu 1, 70210 Kuopio, Finland.
  • 9 CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, CA 90045, USA.
PMID: 27916455 DOI: 10.1016/j.neuron.2016.10.064
Abstract

Huntington's disease (HD) symptoms are driven to a large extent by dysfunction of the basal ganglia circuitry. HD patients exhibit reduced striatal phoshodiesterase 10 (PDE10) levels. Using HD mouse models that exhibit reduced PDE10, we demonstrate the benefit of pharmacologic PDE10 inhibition to acutely correct basal ganglia circuitry deficits. PDE10 inhibition restored corticostriatal input and boosted cortically driven indirect pathway activity. Cyclic nucleotide signaling is impaired in HD models, and PDE10 loss may represent a homeostatic adaptation to maintain signaling. Elevation of both cAMP and cGMP by PDE10 inhibition was required for rescue. Phosphoproteomic profiling of striatum in response to PDE10 inhibition highlighted plausible neural substrates responsible for the improvement. Early chronic PDE10 inhibition in Q175 mice showed improvements beyond those seen with acute administration after symptom onset, including partial reversal of striatal deregulated transcripts and the prevention of the emergence of HD neurophysiological deficits. VIDEO ABSTRACT.

Keywords

MP-10; PDE10A; PF-02545920; Q175; R6/2; cAMP; cGMP; corticostriatal; cyclic nucleotide; subthalamic nucleus.

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