Modulating fear extinction memory by manipulating SK potassium channels in the infralimbic cortex.
Modulating fear extinction memory by manipulating SK potassium channels in the infralimbic cortex.
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DOI：
10.3389/fnbeh.2014.00096
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发表时间：
2014
影响因子：
3
通讯作者：
Porter JT
中科院分区：
文献类型：
--
作者：
Criado-Marrero M;Santini E;Porter JT
恐惧消退与边缘下（IL）神经元兴奋性增加相关。由于小电导Ca2+依赖性K+（SK）通道调节神经元兴奋性和某些类型的学习和记忆，因此SK通道的药理学调节可用于调节IL兴奋性和恐惧消退。为了测试这一点，我们首先确定了用apamin阻断SK通道对脑切片中IL锥体神经元的内在兴奋性的影响。在全细胞膜片钳记录中，apamin增加了由去极化电流脉冲引起的尖峰的数量，增加了放电频率，并降低了快后超极化电位（fAHP），表明SK通道的阻断可用于增强IL神经元的内在兴奋性。接下来，我们评估是否SK通道在IL调节灭绝的条件性恐惧，通过注入apamin到IL的恐惧条件大鼠灭绝训练之前。Apamin输注不影响条件冻结在灭绝会话或会话内灭绝的开始。然而，第二天，注射apamin的大鼠表现出明显较少的条件性冻结。为了进一步研究IL中SK通道在恐惧消退中的重要性，我们评估了SK通道激活剂DCEBIO对IL神经元兴奋性和恐惧消退的影响。用DCEBIO激活SK通道可减少IL神经元的诱发棘波数目，降低放电频率，并增强fAHP。在恐惧消退之前将DCEBIO输注到IL中会损害恐惧消退的回忆，而不影响消退的获得。总之，这些发现表明，SK通道参与调节IL兴奋性和抑制诱导的可塑性。因此，SK通道是一个潜在的目标，为发展新的药物治疗，以促进灭绝的患者患有焦虑症。
Fear extinction correlates with increased infralimbic (IL) neuronal excitability. Since small conductance Ca2+-dependent K+ (SK) channels modulate neuronal excitability and certain types of learning and memory, pharmacological modulation of SK channels could be used to regulate IL excitability and fear extinction. To test this, we first determined the effect of blocking SK channels with apamin on the intrinsic excitability of IL pyramidal neurons in brain slices. In whole-cell patch-clamp recordings, apamin increased the number of spikes evoked by a depolarizing current pulse, increased the firing frequency, and reduced the fast afterhyperpolarizing potential (fAHP) indicating that blockade of SK channels could be used to enhance the intrinsic excitability of IL neurons. Next, we assessed whether SK channels in IL regulate extinction of conditioned fear by infusing apamin into IL of fear conditioned rats prior to extinction training. Apamin infusion did not affect conditioned freezing at the beginning of the extinction session or within-session extinction. However, the following day, apamin-infused rats showed significantly less conditioned freezing. To further examine the importance of SK channels in IL in fear extinction, we assessed the effect of the SK channel activator DCEBIO on IL neuronal excitability and fear extinction. Activation of SK channels with DCEBIO decreased the number of evoked spikes, reduced the firing frequency, and enhanced the fAHP of IL neurons. Infusion of DCEBIO into IL prior to fear extinction impaired recall of fear extinction without affecting acquisition of extinction. Taken together, these findings suggest that SK channels are involved in regulating IL excitability and extinction-induced plasticity. Therefore, SK channels are a potential target for the development of new pharmacological treatments to facilitate extinction in patients suffering from anxiety disorders.
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