Plasticity in the Developing Brain Limits and Magnifies Clinical Disorders

SANTA CLARA, CA—The high degree of plasticity in the developing brain is critical to its ability to organize and develop structure for learning and memory. However, the exaggerated plasticity during gestation and infancy can increase vulnerability to some forms of injury. For example, this plasticity appears to accentuate the risk of damage from episodes of hypoxia, a cause of permanent disabilities such as cerebral palsy, reported Michael V. Johnston, MD, at the 37th Annual Meeting of the Child Neurology Society.

HYPERPLASTICITY IN THE DEVELOPING BRAIN

“The Achilles’ heel of plasticity in early brain development is that it appears to be a major trigger for asphyxial injury,” asserted Dr. Johnston, Director of the Division of Neurology and Developmental Medicine and the Neuroscience Laboratory at Kennedy Krieger Institute, Johns Hopkins University in Baltimore. He indicated that progress in understanding the complexities of brain plasticity has enormous potential to enhance recovery from injuries or to prevent some injuries from occurring.

In the developing brain, there is a relatively high degree of synaptic excitability, which is mediated by glutamate. However, the transporters responsible for removing glutamate are blood flow and glucose dependent. When blood flow and glucose-fueled energy are inhibited, the combination of elevated levels of glutamate and hypoxia depolarizes synaptic membranes, opening N-methyl-D-aspartate (NMDA) receptors to an influx of calcium. Calcium is toxic to neurons, creating a state of neuronal damage known as excitotoxicity. “In the developing brain, NMDA receptors open more easily and flux more calcium than in a mature brain, and the immature synapses are more vulnerable to injury,” Dr. Johnston explained.

Dr. Johnston described paralysis of glutamate pumps as “the key abnormality” in this cascade of events. The concept that glutamate pumps deprived of glucose will lead to a state of excitotoxicity is not new, but recent work has permitted investigators to distinguish events that drive the process, such as the role of the NMDA receptor and calcium influx, from events that are products of the process. These advances provide the basis for at least conceptualizing how these injuries could be prevented.

“We used to think that excess lactic acid in the developing brain was important as a cause of injury, but this is no longer true,” commented Dr. Johnston. “We now think it is an epiphenomenon of the damage. We also now think edema is another epiphenomenon.” He indicated that due to the hyperplasticity of the developing brain, normal steps such as a prolonged stimulation of NMDA receptors produces activation of oxy­gen free radicals that, in turn, trigger apoptosis-inducing factors from cell mitochondria to induce neuronal cell death. The timeframe for this process ranges from days to weeks, noted Dr. Johnston. “The process is set in motion by asphyxia, but then it assumes a life of its own,” he said. “However, there may be opportunities for latent interventions.”

PREVENTING INJURY IN THE DEVELOPING BRAIN

According to Dr. Johnston, “there is now lots of work under way to develop antagonists that will prevent [brain injury] from occurring.” One of the potential strategies already tested clinically has been delivery of exogenous magnesium, which is believed to inhibit the NMDA receptor, blocking influx of cytotoxic calcium. Case control studies stimulated by work in Dr. Johnston’s laboratory in neonatal rodent models had previously linked the use of magnesium sulfate as a tocolytic agent to prevent premature birth with a reduced likelihood of cerebral palsy. In a large placebo-controlled trial of magnesium in women at risk of preterm birth, the primary end point of a reduction in cerebral palsy and neonatal death was not met. However, magnesium was associated with a reduced rate of a secondary end point of cerebral palsy among survivors (1.9% vs 3.5%).

Despite not showing benefit on the primary end point, the study showed an encouraging reduction in cerebral palsy among survivors, providing support for the premise that prenatal therapies have the potential to prevent hypoxic injury. Dr. Johnston asserted that it might be possible to salvage brain tissue with better inhibitors of NMDA or other glutamate receptors, or by targeting additional steps in the molecular cascade set in motion by these receptors.

Dr. Johnston discussed recent experimental work in knocking out a DNA repair enzyme that is considered important in preserving release of apoptosis-releasing factors. One result in an animal model was a protective effect in males but an absence of a protective effect in females. The sexual dimorphism in this pathway was unexpected but suggests that male neurons are more sensitive than females to excitotoxicity and a pathway to cerebral palsy controlled by apoptosis-inducing factors. This may explain why rates of cerebral palsy in the clinical setting are about 40% higher in males than females. “We believe this is a real and potentially important difference that may lead us to new understanding of the processes,” said Dr. Johnston.

DISORDERS RESULTING FROM IMPAIRED PLASTICITY

In addition to disorders and syndromes mediated by the heightened state of plasticity in the developing brain, Dr. Johnston also discussed neurologic disorders due to impairments of plasticity. Such disorders as fragile X syndrome or Rett syndrome are caused by genetic mutations in the molecular signaling pathways responsible for learning, memory, and plasticity. For example, fragile X syndrome has been linked to defects in synaptic plasticity associated with impaired trafficking of glutamate receptors. Rett syndrome has also been linked to a developmental disorder of expression of glutamate receptors in synapses and disrupted synaptic plasticity.

A better understanding of synaptic abnormalities in these and other similar disorders may lead to potential therapies to prevent or reduce disabilities in children. For example, some investigators are examining the potential of medications that alter glutamate receptor trafficking to improve outcome in children with Fragile X syndrome. At Dr. Johnston’s institution, Sakkubai Naidu, MD, is investigating the potential use of the cough suppressant dextromethorphan to improve synaptic function and behavioral outcome in girls with Rett syndrome.

OPPORTUNITIES FOR INTERVENTION

Exploiting the plasticity of the developing brain also holds potential for improving function in children with cerebral palsy and other acquired disorders. Despite the persistence of sequelae to some injuries of the developing brain, plasticity provides an enormous capacity for adaptation. Proliferation and pruning of synapses and refinement of synaptic connections during the period of gestation and neonatal development probably explain why young children who undergo trauma to the CNS are often able to compensate and adapt. Dr. Johnston cited normal language development in young children who undergo left hemispherectomy for epilepsy as an example of this adaptation.

Understanding normal and abnormal plasticity may lead to research that will correct CNS defects that occur early in development. There are three avenues of such research, according to Dr. Johnston. Although studies of adaptive plasticity aim to understand normal development of brains forming memories and adapting neurocognitive traits in response to encounters with stimuli, the study of impaired plasticity represents the effort to understand inherent or acquired defects in the biochemical processes that control plasticity. The third focus of research is the role of normal or even excessive plasticity in increasing vulnerability of the brain to environmental events, such as hypoxia. Dr. Johnston described this latter type as “events that change the brain for the worse based on the fact that they interact with normal molecular steps intended for good.” To the extent that Dr. Johnston and other researchers can differentiate the molecular and genetic processes that control plasticity, new opportunities to intervene may follow.

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