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Integrins Bidirectionally Regulate the Efficacy of Inhibitory Synaptic Transmission and Control GABAergic Plasticity
Journal of Neuroscience ( IF 4.4 ) Pub Date : 2022-07-27 , DOI: 10.1523/jneurosci.1458-21.2022
Grzegorz Wiera 1 , Patrycja Brzdąk 2 , Anna Maria Lech 2, 3 , Katarzyna Lebida 2 , Jadwiga Jabłońska 2 , Przemysław Gmerek 2, 3 , Jerzy W Mozrzymas 1
Affiliation  

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.

SIGNIFICANCE STATEMENT 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.



中文翻译:


整合素双向调节抑制性突触传递的功效并控制 GABA 能可塑性



几十年来,突触可塑性被认为仅限于兴奋性传递。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期可塑性,但其潜在机制仍不清楚。在此,我们询问包含 β1 或 β3 亚基的整联蛋白介导的信号传导是否可能参与调节 GABA 能突触的功效,包括海马中 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 整合素会诱导稳定的抑制,而抑制 β1 整合素则会增强雄性小鼠 CA1 锥体神经元的 GABA 突触。此外,干扰 β1 或 β3 整合素与细胞外基质相互作用的化合物会阻断 NMDA-iLTP 的诱导。总之,我们提供了第一个证据,证明整合素是调节海马 GABA 能抑制和可塑性内源性调节机制的关键参与者。


意义声明癫痫、精神分裂症和焦虑症只是与抑制性突触传递功能失调相关的几种疾病。 GABA 能突触因其对内源性因子和外源性药物的调节非常敏感而闻名。我们在这里描述整合素,粘附蛋白,在抑制性突触传递的调节中发挥关键作用。具体来说,我们表明干扰整合素依赖性粘附会对 GABA 能 mIPSC 的幅度和频率产生多种影响。含有 β3 亚基的整合素的激活会诱导抑制性长期抑郁,而含有 β1 亚基的整合素的抑制则会诱导 iLTP。我们的结果揭示了控制突触抑制的重要机制,这为使用整合素靶向药物作为 GABA 能突触调节剂开辟了新途径。

更新日期:2022-07-28
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