title: Application of neurophysiological biomarkers for Huntington's disease: evaluating a phosphodiesterase 9A inhibitor.
abstract: Several neurophysiological abnormalities have been described in Huntington's disease, including auditory gating deficit, which are considered to reflect impaired brain information-processing. Since transgenic animal models of Huntington's disease capture basic neuropathology of the disorder, auditory gating was studied in BACHD (line5) transgenic rats and Q175 transgenic mice, together with local field gamma power in the hippocampus and primary auditory cortex. Using clinically equivalent acoustic-stimulation paradigms, impaired auditory gating was detected in transgenic BACHD rats under anesthesia and in freely-moving condition. In addition, transgenic BACHD rats showed a lower level of hippocampal and cortical field gamma band power compared to wild-type counterpart, which might be related to their compromised mitochondrial function. Systemic administration of the recently developed phosphodiesterase 9A (PDE9A) inhibitor PF-04447943 dose-dependently improved gating deficit in transgenic BACHD rats in both brain regions. Q175 mice, including wild-type, heterozygote and homozygote mice showed similarly poor gating, and administration of PF-04447943 was without effect. Treatment of transgenic BACHD rats with daily administration of PF-04447943 (1mg/kg) over 7-days resulted in an improvement in their auditory gating both in the hippocampus and primary auditory cortex as evaluated 24h after the last treatment. In fact, differences in auditory gating between wild-type and transgenic BACHD rats were totally abolished after sub-chronic treatment with the PDE9A inhibitor. Our findings indicate that BACHD transgenic rats show abnormal auditory gating with features resembling those of Huntington's disease patients, which could be considered as potential translational biomarker for drug development in treatment of this disease.
authors.affiliation: Translational Neuropharmacology, Section of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Dávid
authors.initials: D
authors.lastname: Nagy
authors.affiliation: Translational Neuropharmacology, Section of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Francis D
authors.initials: FD
authors.lastname: Tingley
authors.affiliation: Translational Neuropharmacology, Section of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Milan
authors.initials: M
authors.lastname: Stoiljkovic
authors.affiliation: Translational Neuropharmacology, Section of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA. Electronic address: mihaly.hajos@yale.edu.
authors.forename: Mihály
authors.initials: M
authors.lastname: Hajós
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000161:Acoustic Stimulation; D000818:Animals; D001303:Auditory Cortex / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005072:Evoked Potentials, Auditory / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D006816:Huntington Disease / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011720:Pyrazoles / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D055139:Sensory Gating / Q000502:physiology*
chemical_list: C572323:6-(4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo(3,4-d)pyrimidin-4-one; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011744:Pyrimidinones; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C507055:Pde9a protein, mouse; C481508:Pde9a protein, rat
keywords: Auditory gating; EEG; Huntington's disease; PF-04447943; Phosphodiesterase 9A