title: Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington's Disease Models.
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.
authors.affiliation: CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, CA 90045, USA. Electronic address: vahri.beaumont@chdifoundation.org.
authors.forename: Vahri
authors.initials: V
authors.lastname: Beaumont
authors.affiliation: Psychogenics Inc., 100 Philips Parkway, Montvale, NJ 07645, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Psychogenics Inc., 100 Philips Parkway, Montvale, NJ 07645, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Lin
authors.affiliation: Psychogenics Inc., 100 Philips Parkway, Montvale, NJ 07645, USA.
authors.forename: WenJin
authors.initials: W
authors.lastname: Xu
authors.affiliation: Neuroservice, Domaine Saint Hilaire, CS30531, 595 rue Pierre BERTHIER, 13593 Aix-en-Provence Cedex 3, France.
authors.forename: Amyaouch
authors.initials: A
authors.lastname: Bradaia
authors.affiliation: Neuroservice, Domaine Saint Hilaire, CS30531, 595 rue Pierre BERTHIER, 13593 Aix-en-Provence Cedex 3, France.
authors.forename: Esther
authors.initials: E
authors.lastname: Steidl
authors.affiliation: Neuroservice, Domaine Saint Hilaire, CS30531, 595 rue Pierre BERTHIER, 13593 Aix-en-Provence Cedex 3, France.
authors.forename: Melanie
authors.initials: M
authors.lastname: Gleyzes
authors.affiliation: Neuroservice, Domaine Saint Hilaire, CS30531, 595 rue Pierre BERTHIER, 13593 Aix-en-Provence Cedex 3, France.
authors.forename: Kristian
authors.initials: K
authors.lastname: Wadel
authors.affiliation: Neuroservice, Domaine Saint Hilaire, CS30531, 595 rue Pierre BERTHIER, 13593 Aix-en-Provence Cedex 3, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Buisson
authors.affiliation: Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA.
authors.forename: Fernando E
authors.initials: FE
authors.lastname: Padovan-Neto
authors.affiliation: Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA.
authors.forename: Shreaya
authors.initials: S
authors.lastname: Chakroborty
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ward
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Harms
authors.affiliation: Psychogenics Inc., 100 Philips Parkway, Montvale, NJ 07645, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Beltran
authors.affiliation: Psychogenics Inc., 100 Philips Parkway, Montvale, NJ 07645, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Kwan
authors.affiliation: Psychogenics Inc., 100 Philips Parkway, Montvale, NJ 07645, USA.
authors.forename: Afshin
authors.initials: A
authors.lastname: Ghavami
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Centre for Psychiatry Research, R5:02, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Häggkvist
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Centre for Psychiatry Research, R5:02, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Miklós
authors.initials: M
authors.lastname: Tóth
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Centre for Psychiatry Research, R5:02, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Centre for Psychiatry Research, R5:02, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Varrone
authors.affiliation: Evotec (München) GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schaab
authors.affiliation: Evotec (München) GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany.
authors.forename: J Nikolaj
authors.initials: JN
authors.lastname: Dybowski
authors.affiliation: Evotec (München) GmbH, Am Klopferspitz 19a, 82152 Martinsried, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Elschenbroich
authors.affiliation: Charles River Discovery, Microkatu 1, 70210 Kuopio, Finland.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Lehtimäki
authors.affiliation: Charles River Discovery, Microkatu 1, 70210 Kuopio, Finland.
authors.forename: Taneli
authors.initials: T
authors.lastname: Heikkinen
authors.affiliation: CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, CA 90045, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Park
authors.affiliation: CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, CA 90045, USA.
authors.forename: James
authors.initials: J
authors.lastname: Rosinski
authors.affiliation: CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, CA 90045, USA.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Mrzljak
authors.affiliation: CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, CA 90045, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lavery
authors.affiliation: Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: West
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schmidt
authors.affiliation: Neuroscience Research Unit, Pfizer, Inc., 610 Main Street, Cambridge, MA 02139, USA.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Zaleska
authors.affiliation: CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, CA 90045, USA.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Munoz-Sanjuan
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases; D049268:Positron-Emission Tomography; D011720:Pyrazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D020531:Subthalamic Nucleus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D014316:Tritium
chemical_list: C545121:2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011804:Quinolines; D014316:Tritium; D000242:Cyclic AMP; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP
keywords: MP-10; PDE10A; PF-02545920; Q175; R6/2; cAMP; cGMP; corticostriatal; cyclic nucleotide; subthalamic nucleus