Establishment and Characterization of Transient Prefrontal Microglia Depletion in Mice

The prefrontal cortex (PFC) is a cortical brain region that is involved in various cognitive functions. One distinctive feature of the PFC is its protracted maturation, which is sustained throughout adolescence until early adulthood and necessary for acquiring mature cognitive abilities. These maturational processes require substantial refinement of neuronal circuitries and synaptic connections, for which microglia may play an important role. The experimental work described in this thesis aimed to investigate the impact of transient microglia deficiency in the mouse PFC on cognitive and synaptic development. To this end, a mouse model was established, in which microglia can be selectively and temporarily depleted from the medial PFC (mPFC) during distinct maturational stages, including preadolescence, adolescence and adulthood. The present experimental work shows that a single intracerebral injection of clodronate disodium salt (CDS) is a suitable and efficient approach to selectively deplete prefrontal microglia without affecting other major cell types in this region. Using this model, it was further found that transient prefrontal microglia deficiency during adolescence induced adult PFC-related cognitive sequelae, including impairments in social recognition memory, temporal order memory and extinction of conditioned fear responses. These deficits were paralleled by morphological and functional changes in the adult prefrontal circuitry, seen as a reduction in dendritic complexity, synaptic structures and an imbalance in excitatory-inhibitory neuronal activity. Intriguingly, CDS injections into the mPFC during preadolescence or adulthood did not induce similar adult cognitive dysfunctions. Taken together, the work described here identifies adolescence as a sensitive period for prefrontal microglia to act on cognitive development