References for this review were identified by searches of PubMed from 1980 until 2006 in September 2006, with special reference to “maturation of transmitters”, “networks”, “synapse formation and their relation to seizures” and “adverse effects on brain development”. Articles were also identified through searches of the authors' personal files. To limit the references to 100, review articles were reviewed after assessing original articles. Only papers published in English were reviewed.
ReviewEffects of seizures on developmental processes in the immature brain
Introduction
During the first few months of life, children are at a particularly high risk for seizures, with the largest number of new-onset seizure disorders occurring during this time.1, 2 During the birthing process, the infant is at risk for insults that can result in seizures. These insults include birth trauma, hypoxic-ischaemic insults, perinatal acquired infections, intracranial haemorrhages, and metabolic disturbances. In addition to being at a high risk for brain insults, substantial evidence suggests that the immature brain is more susceptible to seizures than the mature brain.3, 4, 5
Any attempt to discuss seizures in the developing brain is problematic because of the intrinsic heterogeneity of developing neurons and the inherent difficulty of finding basic common rules that transcend differences between species and developmental stages. Thus, although two adjacent adult pyramidal neurons might look identical, in utero these same two neurons can differ substantially, with one having many synapses and the other no dendrites or active synapses. This is particularly true for primate and human neurons; because of the long gestation period. Nevertheless, recent animal studies have led to advances in answering three essential questions: why seizures are more common during early life than adulthood; how early-life seizures lead to persistent deleterious effects; and why the effects of seizures are age dependent? The main emphasis of this Review is to examine how frequent or severe early-life seizures modify the development of neuronal circuits, thereby increasing the risk for subsequent seizures and adverse behavioural outcome. Not all seizures, particularly those that are infrequent or brief, are harmful. However, it is important to think about the adverse effects of seizures on brain development so that potential interventions can be considered.
In this Review, we concentrate on these issues and stress how they will improve our understanding of epilepsy in the developing brain. Animal models can only give a limited view of the complexity of human clinical data, but electroencephalographic, molecular, and morphological features of epilepsies can usually transcend interspecies differences.
Section snippets
High incidence of seizures in developing brain
The propensity for seizures or seizure-like activity in the immature brain has been shown in several experimental models, including kainic acid,6, 7 electrical stimulation,8 hypoxia,9 penicillin,10 picrotoxin,11 GABABreceptor antagonists,12 and increased extracellular potassium.13, 14 The underlying mechanisms responsible for the increased excitability in the immature brain are not completely understood but are age dependent. Immature neurons and networks tend to generate periodic discharge and
Maturation of cortical networks
During the development of cortical networks, there is a sequential shift from an ensemble of immature cells with little or no organised communication devices to an active network composed of neurons with thousands of active synapses. This shift is mediated by a series of events that includes both intrinsic and extrinsic factors. Like other insults, seizures can modify these pathways and this leads to persistent deleterious effects. Therefore, it is essential to identify these developmental
GABAergic synapses are formed before glutamatergic synapses
Studies that use both GABA receptor antagonists and neuronal reconstruction showed that GABAergic synapses are formed first and glutamate synapses subsequently.19, 46 This applies to neonatal rodents47 and in utero primate central neurons.16 GABA also has an important trophic role in the modulation of dendrite extension and neuronal arborisation.48, 49 Because of the intrinsic heterogeneity of neurons during early development, the actions of GABAergic drugs on different neurons will vary. Thus,
A primitive oscillation pattern in developing networks
By contrast to adult networks, which have a plethora of behaviourally relevant oscillations, immature networks initially show a single primitive pattern of giant depolarising potentials that is present in all developing networks and animal species, including in-utero primates and premature infants.16, 18, 19, 55 This is the only activity in the developing hippocampus until the end of the first postnatal week when it disappears in parallel with GABA's excitatory to inhibitory shift. In other
Differences between developing and adult networks
Animal studies have shown that the pathophysiological consequences of both status epilepticus and recurrent seizures in the developing brain differ substantially from those of the mature brain.57
In adult animals, status epilepticus causes neuronal loss in the hippocampal regions CA1, CA3, and the dentate hilus.58 In addition to cell death, prolonged seizures in the adult brain lead to synaptic reorganisation with aberrant growth (sprouting) of granule cell axons (the so-called mossy fibres) in
Recurrent seizures
As with prolonged seizures, recurrent seizures in infants and children can be harmful.88, 89 Several studies have shown that recurrent seizures during early development can result in long-term morphological and behavioural changes.90, 91, 92
Neonatal seizures induced in rats by the inhalant flurotyl at days 1–5 caused impairment of visual spatial memory in the Morris water maze—a measure of visual-spatial memory.93 When recurrent seizures were induced by flurotyl in animals at day 15–20,
Seizures beget seizures: confirming an old concept
One of the strongest indications that seizures can reliably lead to long-lasting effects is the transformation of a naive network by seizures to one that has increased seizure susceptibility. The distinguished neurologist William Gowers98 noted: “The tendency of the disease [epilepsy] is to self-perpetuation; each attack facilitates the occurrence of another, by increasing the instability of the nerve elements.” Direct support for Gowers' idea that seizures beget seizures emerged from the
Conclusions
Recurrent seizures are more readily generated in immature networks than in adult networks. Although most children with epilepsy do well and eventually outgrow their seizures,107, 108 some will have long-lasting effects. Experimental evidence suggests that the adverse effects of frequent or prolonged seizures at an early stage are primarily due to their interference with developmental programmes rather than cell loss because developing networks are quite resistant to brain damage. This implies
Search strategy and selection criteria
References (108)
Effects of seizures on brain development: lessons from the laboratory
Pediatr Neurol
(2005)- et al.
Maturation of kainic acid seizure-brain damage syndrome in the rat I: clinical, electrographic and metabolic observations
Neuroscience
(1984) - et al.
Penicillin-induced epileptogenesis in immature rats CA3 hippocampal pyramidal cells
Dev Brain Res
(1984) - et al.
The ontogeny of excitatory amino acid receptors in the rat forebrain II: kainic acid receptors
Neuroscience
(1990) - et al.
Differential ontogenic development of three receptors comprising the NMDA receptor/channel complex in the rat hippocampus
Exp Neurol
(1990) - et al.
Do prolonged febrile seizures produce medial temporal sclerosis? Hypotheses, MRI evidence and unanswered questions
Prog Brain Res
(2002) - et al.
Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus
Am J Hum Genet
(2001) - et al.
GABA itself promotes the developmental switch of neuronal GABAergic responses from excitation to inhibition
Cell
(2001) - et al.
Modulation of GABAergic transmission by activity via postsynaptic Ca2+-dependent regulation of KCC2 function
Neuron
(2005) - et al.
Cation-chloride co-transporters in neuronal communication, development and trauma
Trends Neurosci
(2003)