TIMP-2 is abundantly expressed by neurons in the cerebral cortex. In vitro, TIMP-2 induces neuronal cell cycle arrest and neurite outgrowth independent of proteolysis by binding to α3β1 integrin. In vivo, mice deficient in TIMP-2 (TIMP-2^-/-) have more nestin-positive progenitor cells and reduced neurite outgrowth. We propose that TIMP-2 maintains neurons in a quiescent, differentiated state. Adult TIMP-2^-/- mice do not exhibit Pavlovian fear conditioning. This suggests that ECM proteolysis is required for the synaptic plasticity underlying learning and memory. Studies are in progress to determine the mechanism underlying the alterations in cell cycle arrest and neurite outgrowth in vivo. If TIMP-2 expression could be repressed in vivo it would have significant implications for the generation of progenitor cells in neuropathologies associated with neuronal cell death.