Department of Anatomy, Physiology, and Genetics, Department of Psychiatry, and Program in Neuroscience, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814.
J Neurosci. 2014 Feb 26;34(9):3130-41. doi: 10.1523/JNEUROSCI.4009-13.2014.
The discovery that even small changes in extracellular acidity can alter the excitability of neuronal networks via activation of acid-sensing ion channels (ASICs) could have therapeutic application in a host of neurological and psychiatric illnesses. Recent evidence suggests that activation of ASIC1a, a subtype of ASICs that is widely distributed in the brain, is necessary for the expression of fear and anxiety. Antagonists of ASIC1a, therefore, have been proposed as a potential treatment for anxiety. The basolateral amygdala (BLA) is central to fear generation, and anxiety disorders are characterized by BLA hyperexcitability. To better understand the role of ASIC1a in anxiety, we attempted to provide a direct assessment of whether ASIC1a activation increases BLA excitability. In rat BLA slices, activation of ASIC1a by low pH or ammonium elicited inward currents in both interneurons and principal neurons, and increased spontaneous IPSCs recorded from principal cells significantly more than spontaneous EPSCs. Epileptiform activity induced by high potassium and low magnesium was suppressed by ammonium. Antagonism of ASIC1a decreased spontaneous IPSCs more than EPSCs, and increased the excitability of the BLA network, as reflected by the pronounced increase of evoked field potentials, suggesting that ASIC1a channels are active in the basal state. In vivo activation or blockade of ASIC1a in the BLA suppressed or increased, respectively, anxiety-like behavior. Thus, in the rat BLA, ASIC1a has an inhibitory and anxiolytic function. The discovery of positive ASIC1a modulators may hold promise for the treatment of anxiety disorders.
细胞外酸度的微小变化通过激活酸感应离子通道（ASICs）改变神经元网络的兴奋性，这一发现可能在多种神经和精神疾病的治疗中有应用价值。最近的证据表明，ASICs 的一种亚型 ASIC1a 的激活对于恐惧和焦虑的表达是必要的，ASICs 在大脑中广泛分布。因此，ASIC1a 的拮抗剂被提出作为治疗焦虑的一种潜在方法。基底外侧杏仁核（BLA）是产生恐惧的核心，焦虑症的特征是 BLA 过度兴奋。为了更好地理解 ASIC1a 在焦虑中的作用，我们试图直接评估 ASIC1a 的激活是否会增加 BLA 的兴奋性。在大鼠 BLA 切片中，低 pH 或铵激活 ASIC1a 会在中间神经元和主神经元中引起内向电流，并显著增加从主细胞记录到的自发性 IPSC，比自发性 EPSC 增加得更多。高钾和低镁诱导的癫痫样活动被铵抑制。ASIC1a 的拮抗剂减少自发性 IPSC 比 EPSC 更多，并增加 BLA 网络的兴奋性，如诱发场电位的明显增加所反映的那样，这表明 ASIC1a 通道在基础状态下是活跃的。体内 BLA 中 ASIC1a 的激活或阻断分别抑制或增加了焦虑样行为。因此，在大鼠 BLA 中，ASIC1a 具有抑制和抗焦虑作用。发现阳性 ASIC1a 调节剂可能为治疗焦虑症带来希望。
