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 GABAA 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.

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 b1 or b3 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 b3 integrin with fibrinogen induced a stable depression, whereas inhibition of b1 integrin potentiated GABAergic synapses at CA1 pyramidal neurons in male mice. Additionally, compounds that interfere with the interaction of b1 or b3 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.

Structural and functional synapse reorganization is one of the key issues of learning and memory mechanisms. Specific proteases, called matrix metalloproteinases (MMPs), play a pivotal role during learning-related modification of neural circuits. Different types of MMPs modify the extracellular perisynaptic environment, leading to the plastic changes in the synapses. In recent years, there has been an increasing interest in the role played by matrix metalloproteinase-3 (MMP-3) in various processes occurring in the mammalian brain, both in physiological and pathological conditions. In this review, we discuss a crucial function of MMP-3 in synaptic plasticity, learning, neuronal development, as well as in neuroregeneration. We discuss the involvement of MMP-3 in synaptic long-term potentiation, which is likely to have a profound impact on experiencedependent learning. On the other hand, we also provide examples of deleterious actions of uncontrolled MMP-3 activity on the central nervous system (CNS) and its contribution to Alzheimer's and Parkinson's diseases (AD and PD). Since the molecular mechanisms controlled by MMP-3 have a profound and diverse impact on physiological and pathological brain functioning, their deep understanding may be crucial for the development of more specific methods for the treatment of neuropsychiatric diseases.