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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.

Sex differences in neuroimmunity as an inherent risk factor