Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington’s Disease Models
| Autor: | Taneli Heikkinen, J. Nikolaj Dybowski, Larry Park, Fernando E. Padovan-Neto, Amyaouch Bradaia, John F. Harms, Vahri Beaumont, Miklós Tóth, Esther Steidl, Sheng Zhong, Margaret M. Zaleska, Kristian Wadel, Ladislav Mrzljak, Kimmo Lehtimäki, Karen M. Ward, Shreaya Chakroborty, Sarah Elschenbroich, Christer Halldin, Andrea Varrone, Christopher J. Schmidt, Afshin Ghavami, WenJin Xu, Ignacio Munoz-Sanjuan, Mei Kwan, Jose Beltran, Bruno Buisson, Christoph Schaab, Jim Rosinski, Daniel J. Lavery, Anthony R. West, Jenny Häggkvist, Melanie Gleyzes, Hai Lin |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Phosphodiesterase Inhibitors Striatum Tritium Indirect pathway of movement Basal Ganglia Mice 03 medical and health sciences Cyclic nucleotide chemistry.chemical_compound 0302 clinical medicine Huntington's disease Subthalamic Nucleus Basal ganglia Cyclic AMP medicine Animals Cyclic GMP Cerebral Cortex Phosphoric Diester Hydrolases General Neuroscience Phosphodiesterase medicine.disease Neostriatum Disease Models Animal Subthalamic nucleus Huntington Disease 030104 developmental biology chemistry Positron-Emission Tomography Quinolines Pyrazoles PDE10A Psychology Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Neuron. 92:1220-1237 |
| ISSN: | 0896-6273 |
| DOI: | 10.1016/j.neuron.2016.10.064 |
| Popis: | Summary 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 |
| Databáze: | OpenAIRE |
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