Department of Biophysics and Neuroscience, Wroclaw Medical University, 50-368 Wroclaw, Poland
Department of Biophysics and Neuroscience, Wroclaw Medical University, 50-368 Wroclaw, Poland.
J Neurosci. 2022 Jul 27;42(30):5830-5842. doi: 10.1523/JNEUROSCI.1458-21.2022. Epub 2022 Jun 14.
For many decades, synaptic plasticity was believed to be restricted to excitatory transmission. However, in recent years, this view started to change, and now it is recognized that GABAergic synapses show distinct forms of activity-dependent long-term plasticity, but the underlying mechanisms remain obscure. Herein, we asked whether signaling mediated by β1 or β3 subunit-containing integrins might be involved in regulating the efficacy of GABAergic synapses, including the NMDA receptor-dependent inhibitory long-term potentiation (iLTP) in the hippocampus. We found that activation of β3 integrin with fibrinogen induced a stable depression, whereas inhibition of β1 integrin potentiated GABAergic synapses at CA1 pyramidal neurons in male mice. Additionally, compounds that interfere with the interaction of β1 or β3 integrins with extracellular matrix blocked the induction of NMDA-iLTP. In conclusion, we provide the first evidence that integrins are key players in regulating the endogenous modulatory mechanisms of GABAergic inhibition and plasticity in the hippocampus. Epilepsy, schizophrenia, and anxiety are just a few medical conditions associated with dysfunctional inhibitory synaptic transmission. GABAergic synapses are known for their extraordinary susceptibility to modulation by endogenous factors and exogenous pharmacological agents. We describe here that integrins, adhesion proteins, play a key role in the modulation of inhibitory synaptic transmission. Specifically, we show that interference with integrin-dependent adhesion results in a variety of effects on the amplitude and frequency of GABAergic mIPSCs. Activation of β3 subunit-containing integrins induces inhibitory long-term depression, whereas the inhibition of β1 subunit-containing integrins induces iLTP. Our results unveil an important mechanism controlling synaptic inhibition, which opens new avenues into the usage of integrin-aimed pharmaceuticals as modulators of GABAergic synapses.
几十年来，人们一直认为突触可塑性仅限于兴奋性传递。然而，近年来，这种观点开始发生变化，现在人们认识到 GABA 能突触表现出不同形式的活动依赖性长时程可塑性，但潜在的机制仍不清楚。在此，我们想知道由β1 或β3 亚基组成的整联蛋白介导的信号是否参与调节 GABA 能突触的效能，包括海马体中 NMDA 受体依赖性抑制性长时程增强（iLTP）。我们发现，纤维蛋白原激活β3 整联蛋白可诱导稳定的抑制，而抑制β1 整联蛋白则增强雄性小鼠 CA1 锥体神经元的 GABA 能突触。此外，干扰β1 或β3 整联蛋白与细胞外基质相互作用的化合物可阻断 NMDA-iLTP 的诱导。总之，我们首次提供证据表明，整联蛋白是调节海马体 GABA 能抑制和可塑性的内源性调节机制的关键因素。癫痫、精神分裂症和焦虑症只是与抑制性突触传递功能障碍相关的几种医学病症。GABA 能突触因其对内源性因素和外源性药理学制剂的调制具有非凡的敏感性而闻名。我们在这里描述了整联蛋白作为黏附蛋白在调节抑制性突触传递中发挥关键作用。具体而言，我们显示，干扰整联蛋白依赖性黏附会导致 GABA 能 mIPSCs 的幅度和频率发生多种变化。激活包含β3 亚基的整联蛋白会诱导抑制性长时程抑制，而抑制包含β1 亚基的整联蛋白会诱导 iLTP。我们的结果揭示了控制突触抑制的一个重要机制，为使用以整联蛋白为靶点的药物作为 GABA 能突触的调节剂开辟了新途径。
