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The indirect pathway hypothesis of schizophrenia: insights from perinatal asphyxia
1Institute of Cell Biology and Neurosciences (IBCN) - National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina.
Insights
Perinatal asphyxia (PA) increases schizophrenia risk by disrupting brain development. PA affects basal ganglia circuits, potentially explaining the link to schizophrenia spectrum disorders (SSD) and positive symptoms.
Area of Science:
- Neuroscience
- Psychiatry
- Developmental Biology
Background:
- Perinatal asphyxia (PA) is linked to schizophrenia spectrum disorders (SSD).
- PA disrupts neurodevelopmental processes relevant to SSD.
- Basal ganglia circuits, especially the indirect pathway, are implicated in both PA and SSD.
Purpose of the Study:
- To explore the mechanistic link between PA and SSD.
- To investigate the role of basal ganglia dysfunction in PA-SSD comorbidity.
Main Methods:
- Review of clinical and experimental research.
- Analysis of neurodevelopmental disruptions caused by PA.
- Examination of basal ganglia circuit function, particularly D2 receptor signaling.
Main Results:
- PA disrupts neurodevelopment, increasing SSD risk.
- PA impacts basal ganglia maturation and indirect pathway function.
- Indirect pathway dysfunction leads to thalamic disinhibition, affecting cortical information filtering.
Conclusions:
- Dysfunction in the basal ganglia indirect pathway, influenced by PA, may be a key mechanism linking PA to SSD.
- This pathway alteration could contribute to the emergence of positive symptoms in SSD.
Abstract:
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.
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