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. The structural requirements of such plasticity and molecular processes involved in this regulation are poorly understood. Specific molecules, including tissue inhibitor of metalloproteinases-2 (TIMP2) have been implicated in serving a pro-plasticity role in the hippocampus, a role that decreases with brain aging. Here, we report that TIMP2 is highly expressed by neurons within the hippocampus and its loss drives changes in cellular programs related to adult neurogenesis and dendritic spine turnover with corresponding impairments in hippocampus-dependent memory. We find that TIMP2 regulates accumulation of extracellular matrix (ECM) around synapses in the hippocampus with concomitant hindrance in migration of newborn neurons through a denser ECM network. A conditional TIMP2 KO mouse reveals that neuronal TIMP2 regulates adult neurogenesis, accumulation of ECM, and ultimately hippocampus-dependent memory. 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. Overall design: Bulk RNAseq from hippocampus dissected from WT and TIMP2 KO mice.