Prefrontal microglia deficiency during adolescence disrupts adult cognitive functions and synaptic structures: A follow-up study in female mice

•Intracerebral CDS causes cell-specific, local and transient microglia depletion.•Prefrontal microglia depletion in adolescent female mice disrupts adult cognition.•Prefrontal microglia depletion in adolescent female mice impairs adult synapses.•Prefrontal microglia depletion in adult female mice has no lasting cognitive effect.•Prefrontal microglia depletion in adult female mice has no lasting synaptic effect. The prefrontal cortex (PFC) provides executive top-down control of a variety of cognitive processes. A distinctive feature of the PFC is its protracted structural and functional maturation throughout adolescence to early adulthood, which is necessary for acquiring mature cognitive abilities. Using a mouse model of cell-specific, transient and local depletion of microglia, which is based on intracerebral injection of clodronate disodium salt (CDS) into the PFC of adolescent male mice, we recently demonstrated that microglia contribute to the functional and structural maturation of the PFC in males. Because microglia biology and cortical maturation are partly sexually dimorphic, the main objective of the present study was to examine whether microglia similarly regulate this maturational process in female mice as well. Here, we show that a single, bilateral intra-PFC injection of CDS in adolescent (6-week-old) female mice induces a local and transient depletion (70 to 80% decrease from controls) of prefrontal microglia during a restricted window of adolescence without affecting neuronal or astrocytic cell populations. This transient microglia deficiency was sufficient to disrupt PFC-associated cognitive functions and synaptic structures at adult age. Inducing transient prefrontal microglia depletion in adult female mice did not cause these deficits, demonstrating that the adult PFC, unlike the adolescent PFC, is resilient to transient microglia deficiency in terms of lasting cognitive and synaptic maladaptations. Together with our previous findings in males, the present findings suggest that microglia contribute to the maturation of the female PFC in a similar way as to the prefrontal maturation occurring in males.