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Mechanisms of hypoxic neurodegeneration in the developing brain
Michael V Johnston1, Wako Nakajima, Henrik Hagberg
1Department of Neurology and Pediatrics and Kenedy Kreger Research Institute, John Hopkins University School of Medicine, Baltimore, Maryland 21205,USA. Johnston@kennedykrieger.org
Insights
Neonatal brain injury, often caused by asphyxia, leads to neurodevelopmental disorders. Immature neurons
Area of Science:
- Neuroscience
- Developmental Biology
- Neurology
Background:
- Asphyxia and other brain insults cause human neurodevelopmental disorders.
- Neonatal brain injury patterns differ from adult patterns, with significant regional vulnerability.
- Developing brains exhibit unique vulnerabilities compared to mature brains.
Purpose of the Study:
- To investigate the molecular mechanisms underlying selective vulnerability in the developing brain to injury.
- To understand how developmental changes in neurotransmitter circuits and neuronal death pathways contribute to neonatal brain injury.
Main Methods:
- Analysis of developmental changes in excitatory glutamate neurotransmitter circuits.
- Investigation of neuronal death pathways, specifically apoptosis versus necrosis, in immature neurons.
- Examination of the role of NMDA receptors and caspase-3 expression during critical developmental periods.
Main Results:
- Developmental up-regulation of NMDA receptors with enhanced function is observed.
- Increased expression of caspase-3 occurs during critical developmental periods.
- These molecular changes, while promoting plasticity, create vulnerabilities during brain energy crises.
Conclusions:
- Developmental changes in glutamate circuits and apoptosis contribute to selective neonatal brain injury.
- Enhanced NMDA receptor function and caspase-3 expression are key molecular mechanisms.
- These developmental adaptations can paradoxically increase susceptibility to injury under energy-compromised conditions.
Abstract:
Asphyxia and other insults to the developing brain are responsible for several human neurodevelopmental disorders. The pattern of neonatal brain injury differs from that seen in the adult nervous system, and there are wide differences in regional vulnerability. Recent evidence suggests that two events that contribute to this pattern of selective vulnerability are developmental changes in excitatory glutamate-containing neurotransmitter circuits and the propensity for immature neurons to die by apoptosis rather than necrosis. Developmental up-regulation of NMDA receptors with enhanced function and increased expression of caspase-3 at critical periods in development are linked to these mechanisms. Although these molecular changes enhance the developing brain's capacity for plasticity by helping to prune redundant synapses and neurons, they can become "Achilles heels" in the face of a brain energy crisis.