Protein Phosphatase 2A and Glycogen Synthase Kinase 3 Signaling Modulate Prepulse Inhibition of the Acoustic Startle Response by Altering Cortical M-Type Potassium Channel Activity
Protein Phosphatase 2A and Glycogen Synthase Kinase 3 Signaling Modulate Prepulse Inhibition of the Acoustic Startle Response by Altering Cortical M-Type Potassium Channel Activity
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DOI：
10.1523/jneurosci.1292-10.2010
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发表时间：
2010-06-30
影响因子：
5.3
通讯作者：
Heberlein, Ulrike
中科院分区：
文献类型：
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作者：
Kapfhamer, David;Berger, Karen H.;Heberlein, Ulrike
有相当大的兴趣在调节感觉运动门控，因为赤字在这一过程中可能发挥关键作用的精神分裂症和其他精神疾病的症状。感觉运动门控通常在人类和啮齿动物中使用声惊吓反应（PPI）模型的前脉冲抑制进行研究，其中声前脉冲抑制对惊吓诱导刺激的行为输出。然而，PPI的分子和神经机制知之甚少。在这里，我们表明，涉及蛋白磷酸酶2A（PP 2A），糖原合成酶激酶3 β（GSK 3 β），和它们的下游目标，M型钾通道的调节途径，调节PPI。携带编码PP 2A调节亚基的Ppp 2 r5 δ亚型等位基因的小鼠（小家鼠）显示减弱的PPI。这种PPP 2 R5 δ的减少增加了GSK 3 β在丝氨酸9处的磷酸化，这使GSK 3 β失活，表明PPP 2 R5 δ正调节大脑中的GSK 3 β活性。一致地，降低GSK 3 β功能的遗传和药理学操作减弱PPI。M型钾通道亚基KCNQ 2是一种假定的GSK 3 β底物。Kcnq 2的遗传减少也降低了PPI，与linopirdine对M通道的全身抑制一样。重要的是，当直接注入内侧前额叶皮层（mPFC）时，GSK 3抑制剂3-（2，4-二氯苯基）-4-（1-甲基-1H-吲哚-3-基）1H-吡咯-2，5-二酮（SB 216763）和利诺吡啶均降低PPI。mPFC神经元的全细胞电生理记录显示，SB 216763和利诺吡啶对放电具有相似的作用，并且GSK 3抑制闭塞了M通道抑制的作用。这些数据支持一种以前未表征的机制，即PP 2A/GSK 3 β信号调节mPFC中的M型钾通道活性以调节感觉运动门控。
There is considerable interest in the regulation of sensorimotor gating, since deficits in this process could play a critical role in the symptoms of schizophrenia and other psychiatric disorders. Sensorimotor gating is often studied in humans and rodents using the prepulse inhibition of the acoustic startle response (PPI) model, in which an acoustic prepulse suppresses behavioral output to a startle-inducing stimulus. However, the molecular and neural mechanisms underlying PPI are poorly understood. Here, we show that a regulatory pathway involving protein phosphatase 2A (PP2A), glycogen synthase kinase 3 beta (GSK3 beta), and their downstream target, the M-type potassium channel, regulates PPI. Mice (Mus musculus) carrying a hypomorphic allele of Ppp2r5 delta, encoding a regulatory subunit of PP2A, show attenuated PPI. This PPP2R5 delta reduction increases the phosphorylation of GSK3 beta at serine 9, which inactivates GSK3 beta, indicating that PPP2R5 delta positively regulates GSK3 beta activity in the brain. Consistently, genetic and pharmacological manipulations that reduce GSK3 beta function attenuate PPI. The M-type potassium channel subunit, KCNQ2, is a putative GSK3 beta substrate. Genetic reduction of Kcnq2 also reduces PPI, as does systemic inhibition of M-channels with linopirdine. Importantly, both the GSK3 inhibitor 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)1H-pyrrole-2,5-dione (SB216763) and linopirdine reduce PPI when directly infused into the medial prefrontal cortex (mPFC). Whole-cell electrophysiological recordings of mPFC neurons show that SB216763 and linopirdine have similar effects on firing, and GSK3 inhibition occludes the effects of M-channel inhibition. These data support a previously uncharacterized mechanism by which PP2A/GSK3 beta signaling regulates M-type potassium channel activity in the mPFC to modulate sensorimotor gating.