Plasticity in the Neonatal Brain following Hypoxic-Ischaemic Injury

Eridan Rocha-Ferreira, Mariya Hristova, Eridan Rocha-Ferreira, Mariya Hristova

Abstract

Hypoxic-ischaemic damage to the developing brain is a leading cause of child death, with high mortality and morbidity, including cerebral palsy, epilepsy, and cognitive disabilities. The developmental stage of the brain and the severity of the insult influence the selective regional vulnerability and the subsequent clinical manifestations. The increased susceptibility to hypoxia-ischaemia (HI) of periventricular white matter in preterm infants predisposes the immature brain to motor, cognitive, and sensory deficits, with cognitive impairment associated with earlier gestational age. In term infants HI causes selective damage to sensorimotor cortex, basal ganglia, thalamus, and brain stem. Even though the immature brain is more malleable to external stimuli compared to the adult one, a hypoxic-ischaemic event to the neonate interrupts the shaping of central motor pathways and can affect normal developmental plasticity through altering neurotransmission, changes in cellular signalling, neural connectivity and function, wrong targeted innervation, and interruption of developmental apoptosis. Models of neonatal HI demonstrate three morphologically different types of cell death, that is, apoptosis, necrosis, and autophagy, which crosstalk and can exist as a continuum in the same cell. In the present review we discuss the mechanisms of HI injury to the immature brain and the way they affect plasticity.

Figures

Figure 1
Figure 1
Schematic overview of hypoxia-ischaemia pathology. Disruption of blood and oxygen supply results in an initial increase in blood pressure and cerebral blood flow with redistribution favoring the brain, heart, and adrenal glands, as well as reduction in ATP due to limited glucose availability. This results in intracellular accumulation of calcium and cell membrane depolarisation and initial mostly necrotic cell death. During the latent/recovery phase there is normalization of homeostasis. However, if the initial insult is prolonged or severe, this may result within hours in a secondary delayed energy failure, due to disruption of mitochondria function as a result of excitotoxicity, inflammation, and continual uptake of intracellular calcium as well as release of oxygen reactive species. It is during the secondary energy failure that most cell death occurs, with predominant apoptosis. A tertiary phase may occur within days after initial injury and continues for months. This involves late cell death, astrogliosis, remodelling, and repair. Hypothermia, the only clinical treatment available for neonatal encephalopathy, targets the latent phase.
Figure 2
Figure 2
Schematic presentation of the relationship between the different types of cell death. Cell death could be controlled (physiological), including autophagy (caspase-independent) and apoptosis (caspase-dependent), or necrotic. The boundaries between apoptosis, necrosis, and autophagy are not always clear. Apoptotic death is mostly caspase-dependent; however apoptotic morphology can sometimes be registered without obvious caspase activation [136]. Caspase activation can occur through membrane receptor binding (extrinsic) or as a result of metabolic changes following mitochondrial depolarisation (intrinsic) and release of cytochrome C and APAF-1 (adapted from [136]).

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