Temporary Depletion of Microglia during the Early Postnatal Period Induces Lasting Sex-Dependent and Sex-Independent Effects on Behavior in Rats

Abstract

Microglia are the primary immune cells of the brain and function in multiple ways to facilitate proper brain development. However, our current understanding of how these cells influence the later expression of normal behaviors is lacking. Using the laboratory rat, we administered liposomal clodronate centrally to selectively deplete microglia in the developing postnatal brain. We then assessed a range of developmental, juvenile, and adult behaviors. Liposomal clodronate treatment on postnatal days 0, 2, and 4 depleted microglia with recovery by about 10 days of age and induced a hyperlocomotive phenotype, observable in the second postnatal week. Temporary microglia depletion also increased juvenile locomotion in the open field test and decreased anxiety-like behaviors in the open field and elevated plus maze. These same rats displayed reductions in predator odor–induced avoidance behavior, but increased their risk assessment behaviors compared with vehicle-treated controls. In adulthood, postnatal microglia depletion resulted in significant deficits in male-specific sex behaviors. Using factor analysis, we identified two underlying traits—behavioral disinhibition and locomotion—as being significantly altered by postnatal microglia depletion. These findings further implicate microglia as being critically important to the development of juvenile and adult behavior.

Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain

“…Furthermore, masculinization of copulatory behaviour in females by neonatal oestradiol treatment can be prevented by co-treatment with minocycline 43 . Even brief microglial ablation from the neonatal brain of males leads to complete loss of male typical copulatory behaviour in adulthood 52 , along with other sex-specific effects 53 .…”

Microglia: Driving critical periods and sexual differentiation of the brain

“…Liposomal clodronate treatment of male and female pups on PN0, 2 and 4 reduces microglial numbers by 50–80% within 24 h with a full repopulation by PN10 (VanRyzin et al, ). Temporary microglial depletion during development produces significant and long lasting changes to various aspects of behavior in both sexes, which become apparent within a short time period.…”

Myeloid Cells in the Central Nervous System

“…Therefore, mice lacking the complement protein C1q, C3, or complement receptor C3R demonstrate impaired synaptic pruning and connectivity (Schafer et al, 2012; Stevens et al, 2007). Synaptic markers can also be detected in microglia of other brain regions besides the lateral geniculate nucleus, and acute depletion of microglia in development leads to long-lasting changes in adult behavior (Nelson and Lenz, 2017; VanRyzin et al, 2016). Synaptic pruning can also be mediated by the CX3C chemokine receptor 1 (CX3CR1), whose ligand, CX3CL1, is expressed on developing neurons (Paolicelli et al, 2011).…”