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

被引：91

作者：

Beaumont, Vahri ^{[1
]}

Zhong, Sheng ^{[2
]}

Lin, Hai ^{[2
]}

Xu, WenJin ^{[2
]}

Bradaia, Amyaouch ^{[3
]}

Steidl, Esther ^{[3
]}

Gleyzes, Melanie ^{[3
]}

Wadel, Kristian ^{[3
]}

Buisson, Bruno ^{[3
]}

Padovan-Neto, Fernando E. ^{[4
]}

Chakroborty, Shreaya ^{[4
]}

Ward, Karen M. ^{[5
]}

Harms, John F. ^{[5
]}

Beltran, Jose ^{[2
]}

Kwan, Mei ^{[2
]}

Ghavami, Afshin ^{[2
]}

Haggkvist, Jenny ^{[6
]}

Toth, Miklos ^{[6
]}

Halldin, Christer ^{[6
]}

Varrone, Andrea ^{[6
]}

Schaab, Christoph ^{[7
]}

Dybowski, J. Nikolaj ^{[7
]}

Elschenbroich, Sarah ^{[7
]}

Lehtimaki, Kimmo ^{[8
]}

Heikkinen, Taneli ^{[8
]}

Park, Larry ^{[1
]}

Rosinski, James ^{[1
]}

Mrzljak, Ladislav ^{[1
]}

Lavery, Daniel ^{[1
]}

West, Anthony R. ^{[4
]}

Schmidt, Christopher J. ^{[5
]}

Zaleska, Margaret M. ^{[5
]}

Munoz-Sanjuan, Ignacio ^{[1
]}

机构：

[1] CHDI Fdn, CHDI Management, 6080 Ctr Dr, Los Angeles, CA 90045 USA

[2] Psychogenics Inc, 100 Philips Pkwy, Montvale, NJ 07645 USA

[3] Domaine St Hilaire, Neuroserv, CS30531,595 Rue Pierre BERTHIER, F-13593 Aix En Provence 3, France

[4] Rosalind Franklin Univ Med & Sci, 3333 Green Bay Rd, N Chicago, IL 60064 USA

[5] Pfizer Inc, Neurosci Res Unit, 610 Main St, Cambridge, MA 02139 USA

[6] Karolinska Inst, Dept Clin Neurosci, Ctr Psychiat Res, Karolinska Univ Hosp, R5 02, S-17176 Stockholm, Sweden

[7] Evotec Munchen GmbH, Klopferspitz 19a, D-82152 Martinsried, Germany

[8] Charles River Discovery, Microkatu 1, Kuopio 70210, Finland

来源：

NEURON | 2016年 / 92卷 / 06期

关键词：

NEURONAL-ACTIVITY; GENE-EXPRESSION; SPINY NEURONS; NEUROTRANSMISSION; PLASTICITY; STRIATUM; PATHWAY; HAP1; HD;

D O I：

10.1016/j.neuron.2016.10.064

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：1220 / 1237

页数：18

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