Abstract
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.
Highlights
Learning and memory formation have been primarily associated with the plasticity of excitatory glutamatergic synapses [1], the mechanisms of which have been studied for more than four decades [2, 3]
We found that MMP3-dependent extracellular proteolysis plays a central role in postsynaptic GABAergic plasticity that is induced heterosynaptically by short-lasting NMDA stimulation
The expression of inhibitory LTP (iLTP) was accompanied by a larger area of synaptic gephyrin clusters, whereas this phenomenon was not observed when this induction protocol was applied in the presence of the MMP3 inhibitor or in Mmp3−/− neurons
Summary
Learning and memory formation have been primarily associated with the plasticity of excitatory glutamatergic synapses [1], the mechanisms of which have been studied for more than four decades [2, 3]. Inhibitory GABAergic synapses were found to exhibit many forms of long-term plasticity that is putatively important in learning and memory [4, 5]. Plastic changes at GABAergic synapses are thought to regulate numerous phenomena, such as the plasticity of excitatory transmission [6], timing of the auditory critical period [7], stabilization of neuronal dynamics that prevents overexcitation [8], as well as establishment, size and reciprocal interference of engrams [9, 10]. Through the cleavage of identified proteins, matrix metalloproteinase 9
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