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 processes of plasticity in the hippocampus, a role that decreases with brain aging as expression is lost. 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. Consistent with the accumulation of ECM in the hippocampus we observe with aging, we find that TIMP2 acts to reduce accumulation of extracellular matrix (ECM) around synapses in the hippocampus. Moreover, its removal results in hindrance of newborn neuron migration through a denser ECM network. A novel 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.