Neuronal TIMP2 regulates hippocampus-dependent plasticity and extracellular matrix complexity

The functional output of the hippocampus, a brain region subserving memory processes, depends on highly orchestrated cellular and molecular processes that regulate synaptic plasticity throughout life. However, little is known regarding the structural requirements of such plasticity and molecular processes involved in this regulation. Specific molecules, including tissue inhibitor of metalloproteinases-2 (TIMP2) have been implicated in serving a pro-plasticity role within the hippocampus, a role that decreases with brain aging. Here, we report that TIMP2 is expressed at high levels in the hippocampus by neurons and its loss in TIMP2 KO mice drives changes in cellular programs related to adult neurogenesis and dendritic spine turnover with corresponding impairments in hippocampus-dependent memory performance. We find that TIMP2 regulates the accumulation of extracellular matrix (ECM) around synapses in the hippocampus with concomitant hindrance in the migration of newborn neurons through a denser ECM network. Deleting the neuronal pool of TIMP2 using a conditional TIMP2 KO mouse reveals that neuronal TIMP2 regulates adult neurogenesis and hippocampus-dependent memory, as well as accumulation of ECM. Our results define a mechanism whereby hippocampus-dependent function is regulated by TIMP2 and its interactions with the ECM to regulate diverse processes associated with synaptic plasticity.