Piccart Elisabeth, De Backer Jean-François, Gall David, Lambot Laurie, Raes Adam, Vanhoof Greet, Schiffmann Serge, D'Hooge Rudi
Laboratory of Biological Psychology, University of Leuven, 102 Tiensestraat, Leuven B-3000, Belgium.
Laboratory of Neurophysiology, Université libre de Bruxelles, 808 Route de Lennik, Anderlecht, Bruxelles B-1070, Belgium.
Behav Brain Res. 2014 Jul 15;268:48-54. doi: 10.1016/j.bbr.2014.03.016. Epub 2014 Mar 31.
The striatum is the main input structure to the basal ganglia and consists mainly out of medium spiny neurons. The numerous spines on their dendrites render them capable of integrating cortical glutamatergic inputs with a motivational dopaminergic signal that originates in the midbrain. This integrative function is thought to underly attribution of incentive salience, a process that is severely disrupted in schizophrenic patients. Phosphodiesterase 10A (PDE10A) is located mainly to the striatal medium spiny neurons and hydrolyses cAMP and cGMP, key determinants of MSN signaling. We show here that genetic depletion of PDE10A critically mediates attribution of salience to reward-predicting cues, evident in impaired performance in PDE10A knockout mice in an instrumentally conditioned reinforcement task. We furthermore report modest impairment of latent inhibition in PDE10A knockout mice, and unaltered prepulse inhibition. We suggest that the lack of effect on PPI is due to the pre-attentional nature of this task. Finally, we performed whole-cell patch clamp recordings and confirm suggested changes in intrinsic membrane excitability. A decrease in spontaneous firing in striatal medium spiny neurons was found. These data show that PDE10A plays a pivotal role in striatal signaling and striatum-mediated salience attribution.
纹状体是基底神经节的主要输入结构，主要由中等棘状神经元组成。它们树突上众多的棘使其能够将皮质谷氨酸能输入与源自中脑的动机性多巴胺能信号整合起来。这种整合功能被认为是激励显著性归因的基础，而这一过程在精神分裂症患者中会严重受损。磷酸二酯酶10A（PDE10A）主要定位于纹状体中等棘状神经元，并水解环磷酸腺苷（cAMP）和环磷酸鸟苷（cGMP），这两者是中等棘状神经元信号传导的关键决定因素。我们在此表明，PDE10A的基因缺失关键地介导了对奖励预测线索的显著性归因，这在PDE10A基因敲除小鼠在工具性条件强化任务中的表现受损中很明显。我们还报告了PDE10A基因敲除小鼠的潜伏抑制有适度受损，而前脉冲抑制未改变。我们认为对前脉冲抑制缺乏影响是由于该任务的前注意性质。最后，我们进行了全细胞膜片钳记录，并证实了内在膜兴奋性的建议变化。发现纹状体中等棘状神经元的自发放电减少。这些数据表明，PDE10A在纹状体信号传导和纹状体介导的显著性归因中起关键作用。
