Sex-dependent serotonergic signaling across development: molecular mechanisms shaping vulnerability to neurodevelopmental and mental disorders

Psychiatric disorders and several neurodevelopmental conditions, including autism spectrum disorder, display marked sex biases in prevalence, symptom profiles, and treatment response. Converging evidence has positioned the serotonergic system as a key organizer of the brain during development and across the lifespan; however, the principles determining when serotonin acts permissively or instructively remains unresolved. In this Review, we critically examine interventional studies across sensitive developmental and adult windows to assess whether serotonergic signaling acts in a sex-dependent manner to shape circuit architecture and bias vulnerability to neurodevelopmental and psychiatric disorders. We argue that the consequences of serotonergic perturbation depend on developmental timing, biological sex, hormonal context, and circuit identity, rather than solely on serotonin levels. Finally, we discuss how staged interactions among serotonergic signaling, endocrine state, and circuit phenotypes—potentially modulated by RNA-centered regulatory processes—may offer a mechanistically plausible framework through which transient environmental challenges acquire lasting effects on neurodevelopmental and affective vulnerability.