Progranulin suppresses the age-dependent enhancement of neuronal activity in the hypothalamus.

Our previous investigations revealed that progranulin (PGRN) is a lysosomal protein involved in hippocampal neurogenesis and neuroinflammation. However, the possible involvement of PGRN in regulating inflammatory response and mediating neuronal activity is still not well-defined. Here, we demonstrate that PGRN deficiency enhances the age-dependent increase of neuronal activity in the paraventricular nucleus (PVN) of the hypothalamus. Aging increased neuronal activity in the PVN of the hypothalamus, and PGRN deficiency enhanced the effects of age on hypothalamic neuronal activity. Aging increased the lysosomal biogenesis and inflammatory response in microglia, which was also aggravated in PGRN-knockout mice. Moreover, PGRN deficiency enhanced interleukin-1 beta and lysosomal genes levels. These results suggest that PGRN deficiency may enhance the age-dependent increase of neuronal activity possibly because PGRN facilitates immunological responses through regulating lysosomal function.