Microglia along sex lines: From brain colonization, maturation and function, to implication in neurodevelopmental disorders.

In addition to their traditional role as immune sentinels, recent discoveries over the last decade have shown that microglial functions now include regulation of neuronal/glial cell migration, differentiation and maturation, as well as neuronal network formation. It was thus proposed that disruption of these microglial roles, during critical periods of brain development, could lead to the pathological onset of several neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, epilepsy, schizophrenia, and major depressive disorder. The prevalence of these disorders exhibits a clear distinction along sex lines with very little known about the mechanisms underlying this difference.

Translational control of depression-like behavior via phosphorylation of eukaryotic translation initiation factor 4E.

Translation of mRNA into protein has a fundamental role in neurodevelopment, plasticity, and memory formation; however, its contribution in the pathophysiology of depressive disorders is not fully understood. We investigated the involvement of MNK1/2 (MAPK-interacting serine/threonine-protein kinase 1 and 2) and their target, eIF4E (eukaryotic initiation factor 4E), in depression-like behavior in mice. Mice carrying a mutation in eIF4E for the MNK1/2 phosphorylation site (Ser209Ala, Eif4e ki/ki), the Mnk1/2 double knockout mice (Mnk1/2), or mice treated with the MNK1/2 inhibitor, cercosporamide, displayed anxiety- and depression-like behaviors, impaired serotonin-induced excitatory synaptic activity in the prefrontal cortex, and diminished firing of the dorsal raphe neurons.

Prenatal Immune Challenge in Mice Leads to Partly Sex-Dependent Behavioral, Microglial, and Molecular Abnormalities Associated with Schizophrenia.

Epidemiological studies revealed that environmental factors comprising prenatal infection are strongly linked to risk for later development of neuropsychiatric disorders such as schizophrenia. Considering strong sex differences in schizophrenia and its increased prevalence in males, we designed a methodological approach to investigate possible sex differences in pathophysiological mechanisms. Prenatal immune challenge was modeled by systemic administration of the viral mimic polyinosinic-polycytidylic acid (Poly I:C) to C57BL/6 mice at embryonic day 9.

Plasticity of the epigenome during early-life stress.

Early life adversity remains a significant risk factor for the development of a host of negative behavioural and pathological outcomes in adulthood long after the stressor is over. Recent evidence indicates that these lasting effects of ELS may occur via alterations in the epigenetic landscape. Here, we review the main findings of the effects of early life adversity on DNA methylation, histone post-translational modification, and non-coding RNAs in the context of psychiatric disease in animal models and human cohorts.

Prenatal infection leads to ASD-like behavior and altered synaptic pruning in the mouse offspring.

Environmental challenges to the maternal immune system during pregnancy have been associated with an increase in the frequency of neurodevelopmental disorders such as Autism Spectrum Disorders (ASD) appearing in the offspring. Microglia, the brain's resident immune-cells, are now known to be critically involved in normal brain development, shaping connections between neurons by pruning superfluous synaptic spines. Our aim was to investigate whether maternal infection during critical stages of gestation compromises the role of microglia in sculpting neuronal circuits.