Keynote Lecture

Almost 40 years ago we have identified c-Fos, a component of AP-1 transcription factor, as playing a role in learning and memory, i.e., healthy mind. Next, we have identified such c-Fos/AP-1 gene targets in activated neurons as those encoding tissue inhibitor of metalloproteinases-1 (TIMP-1) and matrix metalloproteinase 9 (MMP-9). MMP-9 is an extracellularly operating enzyme that we and others have demonstrated to be an important regulatory molecule in control of synaptic plasticity, learning and memory. We have shown that either genetic or pharmacological inhibition of MMP-9 impairs long-term potentiation at various pathways, as well as appetitive and spatial memory formation, although aversive learning remains apparently intact in MMP-9 KO mice. MMP-9 is locally translated and released from the excitatory synapses in response to neuronal activity. Extrasynaptic MMP-9 is required for growth and maturation of the dendritic spines to accumulate and immobilize AMPA receptors, making the excitatory synapses more efficacious. Our studies on animal models have implicated MMP-9 in such neuropsychiatric conditions, as e.g., epileptogenesis, autism spectrum disorders, development of addiction, schizophrenia and depression. We have also reported that in humans MMP-9 appears to contribute to epilepsy, alcohol addiction, Fragile X Syndrome, schizophrenia and bipolar disorder. In aggregate, all those conditions may be considered as relying on alterations of dendritic spines/excitatory synapses and thus understanding the role played by MMP-9 in the synaptic plasticity may allow to elucidate the underpinnings of major neuropsychiatric disorders, i.e., diseased mind.