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Possible mechanisms in infants for selective basal ganglia damage from asphyxia, kernicterus, or mitochondrial
1Division of Neurology and Developmental Medicine, Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. johnston@kennedykrieger.org
Insights
The basal ganglia
Area of Science:
- Neuroscience
- Neuropathology
- Pediatric Neurology
Background:
- Subregions of the basal ganglia exhibit selective injury patterns in children.
- Conditions like kernicterus and mitochondrial disorders affect the globus pallidus, while perinatal asphyxia impacts the putamen and thalamus.
Observation:
- Differential vulnerability of adjacent basal ganglia nuclei (within millimeters) requires explanation.
- Location within neurotransmitter-specific circuitry of the basal ganglia motor loop is hypothesized to be key.
Findings:
- Severe hypoxic-ischemic encephalopathy overactivates excitatory glutamatergic pathways to the putamen and thalamus.
- The globus pallidus may be protected by inhibitory neuronal activity during severe hypoxia.
- High resting neuronal activity in the globus pallidus may increase vulnerability to oxidative stress from toxins or mitochondrial disorders.
Implications:
- Understanding these mechanisms can guide the development of neuroprotective therapies.
- This knowledge is crucial for managing chronic movement disorders associated with basal ganglia injury.
Abstract:
Magnetic resonance imaging and neuropathologic studies have demonstrated remarkably selective patterns of injury to subregions of the basal ganglia in children. Examples are kernicterus and certain mitochondrial encephalopathies, which cause selective injury to the globus pallidus, and near-total perinatal asphyxia, which causes lesions in the putamen and thalamus. To explain the differential vulnerability of nuclei within millimeters of each other, we hypothesize that their locations within the neurotransmitter-specific circuitry of the basal ganglia motor loop are important. In severe hypoxic-ischemic encephalopathy, excitatory glutamatergic pathways into the putamen and thalamus are overactive, but the globus pallidus might be protected because its activity is silenced by inhibitory neuronal activity. In contrast, the relatively high resting neuronal activity in the globus pallidus might make it more vulnerable to less intense, subacute oxidative stresses from mitochondrial toxins such as bilirubin or from genetic mitochondrial disorders. This hypothesis has implications for designing neuroprotective therapies and for treating associated chronic movement disorders.