Saha Rinki, Knapp Stephanie, Chakraborty Darpan, Horovitz Omer, Albrecht Anne, Kriebel Martin, Kaphzan Hanoch, Ehrlich Ingrid, Volkmer Hansjürgen, Richter-Levin Gal
Sagol Department of Neurobiology, University of Haifa, Haifa, Israel.
Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Neuropsychopharmacology. 2017 Jan;42(2):473-484. doi: 10.1038/npp.2016.205. Epub 2016 Sep 16.
Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its extinction. However, the local circuits formed by GABAergic inhibitory interneurons within the amygdala and their detailed function in shaping these behaviors are not well understood. Here we used lentiviral-mediated knockdown of the cell adhesion molecule neurofascin in the basolateral amygdala (BLA) to specifically remove inhibitory synapses at the axon initial segment (AIS) of BLA projection neurons. Quantitative analysis of GABAergic synapse markers and measurement of miniature inhibitory postsynaptic currents in BLA projection neurons after neurofascin knockdown ex vivo confirmed the loss of GABAergic input. We then studied the impact of this manipulation on anxiety-like behavior and auditory cued fear conditioning and its extinction as BLA related behavioral paradigms, as well as on long-term potentiation (LTP) in the ventral subiculum-BLA pathway in vivo. BLA knockdown of neurofascin impaired ventral subiculum-BLA-LTP. While this manipulation did not affect anxiety-like behavior and fear memory acquisition and consolidation, it specifically impaired extinction. Our findings indicate that modification of inhibitory synapses at the AIS of BLA projection neurons is sufficient to selectively impair extinction behavior. A better understanding of the role of distinct GABAergic synapses may provide novel and more specific targets for therapeutic interventions in extinction-based therapies.
杏仁核中的抑制性突触传递在恐惧学习及其消退中起关键作用。然而，杏仁核内由γ-氨基丁酸（GABA）能抑制性中间神经元形成的局部回路及其在塑造这些行为中的详细功能尚未得到充分了解。在这里，我们使用慢病毒介导的方法敲低基底外侧杏仁核（BLA）中的细胞粘附分子神经束蛋白，以特异性去除BLA投射神经元轴突起始段（AIS）的抑制性突触。对神经束蛋白敲低后的离体BLA投射神经元中GABA能突触标记物进行定量分析，并测量微小抑制性突触后电流，证实了GABA能输入的丧失。然后，我们研究了这种操作对焦虑样行为、听觉线索恐惧条件反射及其消退（作为与BLA相关的行为范式）的影响，以及对体内腹侧下托-BLA通路中长时程增强（LTP）的影响。BLA中神经束蛋白的敲低损害了腹侧下托-BLA-LTP。虽然这种操作不影响焦虑样行为以及恐惧记忆的获得和巩固，但它特异性地损害了消退。我们的研究结果表明，改变BLA投射神经元AIS处的抑制性突触足以选择性地损害消退行为。更好地理解不同GABA能突触的作用可能为基于消退疗法的治疗干预提供新的、更具体的靶点。
