Zaman Tariq, De Oliveira Cleusa, Smoka Mahabba, Narla Chakravarthi, Poulter Michael O, Schmid Susanne
Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada, and.
Physiology and Pharmacology, and Molecular Medicine Research Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada.
J Neurosci. 2017 Apr 26;37(17):4540-4551. doi: 10.1523/JNEUROSCI.3699-16.2017. Epub 2017 Mar 27.
Habituation is a basic form of implicit learning and represents a sensory filter that is disrupted in autism, schizophrenia, and several other mental disorders. Despite extensive research in the past decades on habituation of startle and other escape responses, the underlying neural mechanisms are still not fully understood. There is evidence from previous studies indicating that BK channels might play a critical role in habituation. We here used a wide array of approaches to test this hypothesis. We show that BK channel activation and subsequent phosphorylation of these channels are essential for synaptic depression presumably underlying startle habituation in rats, using patch-clamp recordings and voltage-sensitive dye imaging in slices. Furthermore, positive modulation of BK channels can enhance short-term habituation. Although results using different approaches do not always perfectly align, together they provide convincing evidence for a crucial role of BK channel phosphorylation in synaptic depression underlying short-term habituation of startle. We also show that this mechanism can be targeted to enhance short-term habituation and therefore to potentially ameliorate sensory filtering deficits associated with psychiatric disorders. Short-term habituation is the most fundamental form of implicit learning. Habituation also represents a filter for inundating sensory information, which is disrupted in autism, schizophrenia, and other psychiatric disorders. Habituation has been studied in different organisms and behavioral models and is thought to be caused by synaptic depression in respective pathways. The underlying molecular mechanisms, however, are poorly understood. We here identify, for the first time, a BK channel-dependent molecular synaptic mechanism leading to synaptic depression that is crucial for habituation, and we discuss the significance of our findings for potential treatments enhancing habituation.
习惯化是一种内隐学习的基本形式，代表一种感觉过滤器，在自闭症、精神分裂症和其他几种精神障碍中会受到破坏。尽管在过去几十年里对惊吓反应和其他逃避反应的习惯化进行了广泛研究，但其潜在的神经机制仍未完全了解。先前的研究有证据表明，BK通道可能在习惯化中起关键作用。我们在此使用了多种方法来验证这一假设。我们发现，BK通道的激活及其随后的磷酸化对于大鼠惊吓习惯化背后的突触抑制至关重要，这是通过在脑片中进行膜片钳记录和电压敏感染料成像得出的结论。此外，对BK通道的正向调节可以增强短期习惯化。尽管使用不同方法得到的结果并不总是完全一致，但它们共同为BK通道磷酸化在惊吓短期习惯化背后的突触抑制中的关键作用提供了令人信服的证据。我们还表明，这一机制可以作为靶点来增强短期习惯化，从而有可能改善与精神疾病相关的感觉过滤缺陷。短期习惯化是内隐学习最基本的形式。习惯化也代表了一种对大量感觉信息的过滤，在自闭症、精神分裂症和其他精神疾病中会受到破坏。习惯化已在不同生物体和行为模型中得到研究，被认为是由各自通路中的突触抑制引起的。然而，其潜在的分子机制却知之甚少。我们首次确定了一种依赖BK通道的分子突触机制，该机制导致对习惯化至关重要的突触抑制，并且我们讨论了我们的发现对于增强习惯化的潜在治疗方法的意义。
