The prefrontal cortex (PFC) is a cortical brain region that regulates various cognitive functions. One distinctive feature of the PFC is its protracted adolescent maturation, which is necessary for acquiring mature cognitive abilities in adulthood. Here, we show that microglia, the brain’s resident immune cells, contribute to this maturational process. We find that transient and cell-specific deficiency of prefrontal microglia in adolescence is sufficient to induce an adult emergence of PFC-associated impairments in cognitive functions, dendritic complexity, and synaptic structures. While prefrontal microglia deficiency in adolescence also altered the excitatory-inhibitory balance in adult prefrontal circuits, there were no cognitive sequelae when prefrontal microglia were depleted in adulthood. Thus, our findings identify adolescence as a sensitive period for prefrontal microglia to act on cognitive development.

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Background Aberrant activity of microglia, the primary innate immune cells of the brain parenchyma, may play a role in the etiology and pathophysiology of schizophrenia and related disorders. While current immunopsychiatric research indicates that microglial hyperactivity may contribute to psychotic illness in some cases, the diametrical opposite (i.e. microglial hypoactivity) may be pathologically and therapeutically relevant for others. The latter hypothesis, however, remains largely unexplored and thus warrants investigation. Methods We aimed at developing a model system in mice, in which the short- and long-term effects of selective, temporary and local depletion of microglia can be studied experimentally. This model system is based on intracerebral injection of clodronate disodium salt (CDS) into selected brain areas of interest. The behavioral and cognitive effects of temporary microglia depletion in the adolescent medial frontal cortex (mPFC) were assessed after full microglia recovery in adulthood. In addition, genome-wide transcriptional profiling was conducted during the peak of microglia depletion and after full microglia recovery in the mPFC. Results We show that a single intracerebral injection of CDS is a suitable and efficient approach to selectively deplete microglia without affecting astrocytes and neurons in-vivo, leading to a robust (~ 80% depletion) but temporary (~ 1 week) microglia deficiency in selected brain areas of interest. Using this model, we further demonstrate that CDS injection into mPFC during late adolescence (6 weeks of age) causes numerous mPFC-related cognitive dysfunctions in adulthood, that is, when microglial cells have been fully restored again. The spectrum of cognitive deficits included impairments in social recognition memory, temporal order memory and extinction of conditioned fear responses. These deficits emerged similarly in male and female animals and were paralleled by a permanent transcriptional dysregulation of genes relevant for synaptic refinement and stability. Intriguingly, CDS injections into the mPFC during early adolescence (4 weeks of age) or adulthood (12 weeks of age) did not induce similar cognitive dysfunctions in adulthood. Discussion Taken together, the present data demonstrate that temporary prefrontal microglia deficiency during adolescence leads to permanent cognitive impairments in adulthood. Our findings further highlight that distinct adolescent stages of cortical maturation show a differing sensitivity towards the long-term cognitive effects of temporary microglia hypoactivity.