George Huntley · NACS Seminar: Novel mechanisms for coupling synaptic structural and functional plasticity
Synaptic structural and functional plasticity underlies many forms of enduring behavioral experience, including learning and memory. The molecular mechanisms that drive coordinated remodeling of both synaptic form and function remain mostly undefined. The focus of my talk is on newly recognized roles for matrix metalloproteinases (MMPs) in rapid remodeling of the synaptic microenvironment associated with synaptic and behavioral plasticity. MMPs are a large family of extracellularly-acting, mostly secreted proteases whose targets include extracellular matrix (ECM), adhesion proteins and other cell-surface molecules that are important for maintaining and modifying synaptic architecture. I summarize here our recent work showing that MMP-9 is rapidly upregulated and becomes proteolytically active in hippocampus by stimuli that induce certain long-lasting forms of synaptic plasticity, as well as by a single-trial, inhibitory-avoidance learning experience. Once proteolytically active, MMPs signal though integrin receptors both to potentiate synapses and concomittantly to enlarge the spine-heads in which they sit. These processes require dynamic actin and modification of certain actin-binding proteins. When MMP function is abrogated genetically or pharmacologically, stable functional and structural synaptic plasticity as well as hippocampal-dependent memory are significantly impaired. Together these data provide compelling support for the idea that MMPs function in normal synaptic physiology, coordinating both synaptic structural and functional plasticity appropriate for enabling memory.