ReviewUsing mouse models to investigate sex-linked genetic effects on brain, behaviour and vulnerability to neuropsychiatric disorders

Many brain and behavioural phenotypes in humans exhibit some degree of sexual dimorphism. Moreover, there are large and replicable differences in the vulnerability of the two sexes to a wide range of common brain disorders. Ultimately, sex differences in healthy individuals, or in pathological states, must arise as a consequence of the differential complement of sex-linked genes in males and females. These genes may act indirectly (for example through influencing gonadal hormone secretion), or directly, to influence brain development and function. In this review, I discuss how genetically tractable mouse models may be employed to inform our knowledge of the molecular basis of sexual differentiation of the mammalian brain, and how such models may therefore represent a useful tool through which to identify risk factors predisposing to sex-biased neuropsychiatric disorders.

► Sex differences are evident across a number of psychological domains in healthy individuals. ► Sex differences in incidence, course, response to therapy and underlying neurobiology are seen in many common neuropsychiatric disorders. ► These sex differences must stem from sex differences in the complement of genes on the X and Y chromosomes. ► Through using mouse models we may begin to understand how the sex-linked genetic complement may act to influence sex-specific neurobiology, and sex-biased vulnerability to psychiatric disorders. ► The identification and characterisation of risk/protective factors for behavioural abnormalities in such models should ultimately allow us to design more effective therapies against novel targets.