The indirect pathway hypothesis of schizophrenia: insights from perinatal asphyxia

The comorbidity between perinatal asphyxia (PA) and schizophrenia spectrum disorders (SSD) has been consistently documented in both clinical and experimental research. Individuals exposed to PA show an increased risk of developing long-term neuropsychiatric conditions, including SSD. Experimental models reveal that PA disrupts neurodevelopmental processes also altered in SSD. Moreover, converging evidence indicates that PA can affect the maturation and functional balance of basal ganglia circuits, particularly the indirect pathway, which relies heavily on D2 receptor–mediated signaling and is consistently implicated in the pathophysiology of SSD. Alterations in this pathway may therefore represent a mechanistic link contributing to the shared vulnerability between PA and SSD, where thalamic disinhibition resulting from indirect pathway dysfunction reduces the filtering of information relayed from the thalamus to the cortex, thereby facilitating the emergence of positive symptoms.