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. Bulk RNAseq from hippocampus dissected from WT and TIMP2 KO mice.海马体（hippocampus）是负责记忆加工的脑区，其功能输出依赖于高度协同的细胞与分子过程——这些过程终生调控突触可塑性（synaptic plasticity）。目前学界对这类可塑性的结构基础，以及该调控过程所涉及的分子机制仍知之甚少。包括金属蛋白酶组织抑制剂-2（tissue inhibitor of metalloproteinases-2, TIMP2）在内的特定分子，已被证实可在海马体中发挥促突触可塑性的作用，且该作用随脑衰老而逐渐减弱。 本研究发现，TIMP2在海马体神经元中高表达；其缺失会引发与成年神经发生（adult neurogenesis）及树突棘周转（dendritic spine turnover）相关的细胞程序改变，并导致海马依赖型记忆功能受损。我们还发现，TIMP2可调控海马体突触周围细胞外基质（extracellular matrix, ECM）的沉积，同时会因细胞外基质网络更为致密，而阻碍新生神经元的迁移。 条件性TIMP2敲除（KO）小鼠实验证实，神经元来源的TIMP2可调控成年神经发生、细胞外基质沉积，并最终影响海马依赖型记忆功能。本研究结果揭示了一条调控海马体功能的新机制：TIMP2通过与细胞外基质相互作用，调控与突触可塑性相关的多种生物学过程。 本研究的数据集包含野生型（WT）与TIMP2敲除小鼠的海马体解剖组织的批量RNA测序（bulk RNAseq）数据。