Sex differences in neuroimmunity as an inherent risk factor

Abstract

Identifying and understanding the sources of inherent risk to neurodevelopmental disorders is a fundamental goal of neuroscience. Being male or being exposed to inflammation early in life are two known risk factors, but they are only infrequently associated with each other. Cellular and molecular mechanisms mediating the masculinization of the brain in animal models reveal a consistent role for inflammatory signaling molecules and immune cells in the healthy male brain. Why this is so remains in the realm of speculation but may have its origins in the maternal immune system. Masculinization of the brain occurs during a restricted critical period that begins in utero and overlaps with the sensitive period during which maternal immune activation negatively impacts the developing brain. The convergence of maleness and early life inflammation as risk factors for neuropsychiatric disorders compels us to consider whether sexual differentiation of the brain in males creates an inherent and greater risk than that experienced by females.

Fig. 1

Sensitive and critical periods in brain development. The developing brain is characterized by epochs during which essential stimuli direct cell survival and synaptic patterns, thereby programming the brain during a critical period. Sensitive periods may overlap with critical periods but also include times during which aberrant or exogenous stimuli can alter the normal developmental trajectory. Sexual differentiation of the brain includes a critical period during which endogenous testosterone from the fetal testis masculinizes the brain. Females remain sensitive to the masculinizing effects of exogenous testosterone into the first week of life, albeit it requiring increasingly larger doses (indicated by larger arrows). The brain is also sensitive to immune activation, either via sickness in the mother or directly to the newborn, during a restricted period that is still being understood. Importantly, the critical period for masculinization of the brain and the sensitive period to inflammation overlap and may contribute to sex differences in risk of developmental neuropsychiatric disorders

Fig. 2

Higher inflammation in developing male brains as an inherent risk factor. Cellular mechanisms mediating masculinization of the brain frequently involve elevated levels of inflammatory signaling molecules and immune cells. Early life exposure to inflammation is a documented risk factor for developmental neuropsychiatric disorders. Being male is also a documented risk factor, suggesting there may be a convergence in the normal process of masculinization and environmental events increasing risk. PGE2 prostaglandin E2, 2-AG endocannabinoid