Learning and memory are known to depend on synaptic plasticity. Whereas the involvement of plastic changes at excitatory synapses is well established, plasticity mechanisms at inhibitory synapses only start to be discovered. Extracellular proteolysis is known to be a key factor in glutamatergic plasticity but nothing is known about its role at GABAergic synapses. We reveal that pharmacological inhibition of MMP3 activity or genetic knockout of the Mmp3 gene abolishes induction of postsynaptic iLTP. Moreover, the application of exogenous active MMP3 mimics major iLTP manifestations: increased mIPSCs amplitude, enlargement of synaptic gephyrin clusters, and a decrease in the diffusion coefficient of synaptic GABA_A receptors that favors their entrapment within the synapse. Finally, we found that MMP3 deficient mice show faster spatial learning in Morris water maze and enhanced contextual fear conditioning. We conclude that MMP3 plays a key role in iLTP mechanisms and in the behaviors that presumably in part depend on GABAergic plasticity.

已知学习和记忆依赖于突触可塑性。众所周知，在兴奋性突触中涉及塑性变化，而在抑制性突触中仅发现可塑性机制。已知细胞外蛋白水解是影响谷氨酸能可塑性的关键因素，但对其在GABA能突触中的作用一无所知。我们揭示，MMP3活性或Mmp3基因的基因敲除的药理抑制作用消除了突触后iLTP的诱导。此外，外源活性MMP3的应用模仿了主要的iLTP表现：增加的mIPSC振幅，突触的gephyrin团簇增大以及突触的GABA _A扩散系数降低。有利于它们在突触中截留的受体。最后，我们发现缺乏MMP3的小鼠在莫里斯水迷宫中显示出更快的空间学习能力，并增强了情境恐惧条件。我们得出结论，MMP3在iLTP机制和可能部分取决于GABA能可塑性的行为中起着关键作用。