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Neurotransmitters and vulnerability of the developing brain
1Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Insights
The developing brain has critical periods of vulnerability due to ongoing organizational changes. Understanding these windows helps explain neuropathology in infants and fetuses.
Area of Science:
- Neuroscience
- Developmental Biology
- Pediatric Neurology
Background:
- The immature human brain undergoes significant organizational changes during development.
- These changes create specific temporal windows of vulnerability to injury.
- Examples include germinal matrix hemorrhage and periventricular leukomalacia.
Purpose of the Study:
- To explain neuropathology in the developing brain based on organizational principles.
- To highlight the selective vulnerability of the immature brain to certain insults.
- To discuss the role of developmental changes in synaptic plasticity and receptor function.
Main Methods:
- Review of developmental neurobiology principles.
- Analysis of synaptic development and glutamate receptor changes.
- Correlation of developmental changes with neuropathological outcomes.
Main Results:
- Immature brains exhibit unique vulnerabilities, such as germinal matrix hemorrhage and periventricular leukomalacia.
- Synaptic development involves overproduction followed by pruning, with altered glutamate receptor (NMDA) characteristics.
- Immature NMDA receptors are more easily activated and stay open longer, increasing vulnerability to excitotoxicity.
Conclusions:
- Developmental organizational principles explain selective neuropathological vulnerabilities in the immature brain.
- Changes in synaptic structure and function, particularly NMDA receptor properties, contribute to injury susceptibility.
- Understanding these principles is crucial for diagnosing and potentially preventing brain injury in neonates and fetuses.
Abstract:
The immature human brain undergoes remarkable organizational changes during intrauterine and postnatal life. These changes create potential temporal 'windows' of selective vulnerability to damage. For example, the temporary germinal matrix is vulnerable to hemorrhage in the third trimester fetus and premature infant. The immature oligodendroglia present in developing white matter of the fetus are also vulnerable to injury producing periventricular leukomalacia. Similar changes take place in the synapses that make up the infant's neuronal circuitry. In human cerebral cortex, synapses are produced in greater than adult numbers by postnatal age 2 years and then reduced over the next decade. Over the same period receptors for glutamate, the most important excitatory neurotransmitter, change their characteristics to allow them to participate in activity dependent synaptic plasticity. For example, the immature N-methyl-D-aspartate (NMDA) type glutamate receptor/channel complex, which plays important roles in long term potentiation (LTP), neuronal migration and synaptic pruning, contains subunits that allow the channel to be opened more easily for a longer period than adult channels. These developmental changes make the immature brain selectively vulnerable to NMDA receptor overstimulation that can occur during hypoxia-ischemia and other insults. Several types of neuropathology in the developing brain can be understood on the basis of these organizational principles.