Chapter 45 - The developing cortex

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Abstract

Cortical maturation is associated with a series of developmental programs encompassing neuronal and network-driven patterns. Thus, voltage-gated and synapse-driven ionic currents are very different in immature and adult neurons with slower kinetics in the former than in the latter. These features are neuron and developmental stage dependent. GABA, which is the main inhibitory neurotransmitter in adult brain, depolarizes and excites immature neurons and its actions are thought to exert a trophic role in developmental processes. Networks follow a parallel sequence with voltage-gated calcium currents followed by calcium plateaux and synapse-driven patterns in vitro. In vivo, early activity exhibits discontinuous temporal organization with alternating bursts. Early cortical patterns are driven by sensory input from the periphery providing a basis for activity-dependent modulation of the cortical networks formation. These features and notably the excitatory GABA underlie the high susceptibility of immature neurons to seizures. Alterations of these sequences play a central role in developmental malformations, notably migration disorders and associated neurological sequelae.

Introduction

There is a general agreement that developing circuits are more readily engaged in seizure manifestations and epilepsies than those in adults. This is validated both in terms of the incidence of seizures and epidemiological studies performed at various developmental stages in a wide range of countries to the extent that epilepsies are considered by some primarily developmental disorders. Yet the agreement appears to stop just there. Why do immature neurons generate seizures? What are the clinical implications? Do seizures lead to long-term sequels and how? Do seizures operate in the developing brain as in the adults or are we dealing with a different event altogether? Is it really justified to use similar therapeutic strategies in children and adults? All these questions are conditioned by our fundamental understanding of the properties of the developing brain. In essence here, perhaps even more than in other domains, the link between basic research on the mechanisms underlying brain development and seizures is all the more instrumental. There have been spectacular advances in developmental neurobiology offering a unique opportunity to develop this field further and correct a number of false assumptions, which has major implications for the above issues; these advances are summarized here. Our message is that early life epilepsies should be examined from a developmental perspective and not from an adult one, taking into account the unique features of the developing brain.

The developing brain is extremely heterogeneous ā€“ far more so than in the adult brain ā€“ since at any given stage, very immature neurons endowed with little or no synapses can coexist with neurons that already have thousands of synapses. Neurons of the human neocortex divide and become postmitotic in a period extending over 100 days, hence 99-day-old neurons will operate with neurons that formed a couple of hours earlier. Seizures when generated exert very different actions on these neurons. The developing brain operates with signals that even when they are identical to those of adults have a different, sometimes even opposite, action. Thus, seizures are generated by some basic features of immature neurons, which tend to oscillate, and the unique actions of the inhibitory transmitter GABA, which excites immature neurons because of a higher intracellular concentration of chloride. Virtually all voltage and transmitter gated currents differ in young and adult neurons. Immature signals tend be inaccurate and long lasting when compared to adult signals because of a developmental sequence of expression of subunits. This leads to a jittery nonprecise generation of spikes in response to a synapse driven stimulus and this is also known to facilitate the generation of seizures. These observations suggest that drugs used in adult brains can have different, even opposite, actions in young patients. Also, immature networks will react differently to insults and seizures than adult networks: whereas adult circuits operate by means of cell loss and reactive plasticity, immature neurons are far more resistant to damage than adults. However, seizures do lead to long-terms deleterious sequels in young brains, which are mediated by alterations of developmental programs rather than cell loss. The programmatic versus lesion-related response to seizures has major implications in that misplaced, misconnected, or maldeveloped neurons may be a unifying link between seizures of the immature brain that in turn impact the operation of cortical maps and functional units. Hence the importance of examining in more detail the outcome of seizures on developing functional cortical units.

Section snippets

Developing neurons and networks follow a developmental sequence

The formation of the adult networks with their plethora of behaviorally relevant oscillations and patterns takes time and follows a sequence. Ionic channels and network driven patterns do not appear randomly but obey a precisely timed sequence. Thus, at the cellular level, neurons first express calcium currents and a variety of potassium currents followed by sodium currents (Spitzer, 1994, Moody and Bosma, 2005). Furthermore, the subunits that generate these currents also follow a sequence

Why do immature networks generate seizures more readily?

There are several reasons why immature networks are intrinsically more prone to generate oscillations and seizures than adults. Immature neurons are electrically compact, have a higher input resistance and small capacitance, and generate larger membrane potential responses to smaller currents. As a consequence, even with a smaller number of connections, immature neurons more readily generate synchronized activities. Also, because of their sloppy ionic currents characterized by long-lasting

Seizures beget seizures in the developing brain

To determine the effects of seizures on immature networks, we developed an intact in vitro preparation consisting of the two intact interconnected hippocampi placed in a chamber with three compartments (Khazipov et al., 1999). Each hippocampus is placed in a separate compartment and the connecting commissures in the third chamber. With this arrangement, each compartment can be perfused with different liquids and their effects investigated. Thus, kainate or another convulsive agent is applied to

The reactive plasticity sequence of events generated by seizures

In adults: Extensive investigations in adults show that recurrent seizures generate a brain damage syndrome with a pattern of cell loss that is reminiscent of that observed in TLE. Thus, administration of the powerful excitotoxic agent kainate generates seizures with electrographic and clinical signs that are of typical limbic symptomatology followed by damage in vulnerable zones that include the CA3 regions of the hippocampus and various neuronal populations in the limbic system (Ben-Ari, 1985

All developmental steps are activity and receptor dependent

The formation of an operative brain with a plethora of behaviorally relevant oscillations and integrative functional units and ensembles is organized around a series of steps including cell proliferation, neuronal migration, neuronal differentiation, and synapse formation followed by the construction of functional units and the elimination of superfluous neurons and connections. All these steps are modulated by electrical activity and the environment. Thus, activation of GABA receptors controls

Mechanisms underlying the generation of seizures by genetic migration disorders: developmental sequences and cortical maps

A wide range of genetic mutations are associated with migration disorders and other developmental malformations and include severe intractable seizures amongst the neurological sequelae. These mutations implicate a wide range of different proteins including cytoskeletal proteins but also transmitter gated receptors and other important signaling molecules. These disorders offer interesting possibilities for investigating not only the mechanisms underlying seizure generation in these tissues,

Conclusions

Understanding and curing developmental insults requires consideration of the unique sequences of brain development as well as the inherent heterogeneity that characterizes the immature brain. Indeed, the large repertoire of currents and signaling cascades in immature neurons leads to a wide range of possible sequelae to genetic and environmental insults associated with seizures. Signals that alter developmental patterns and retard or block developmental sequences lead to programatic sequelae

References (84)

  • C. Dreyfus-Brisac et al.

    Discontinuous electroencephalograms in the premature newborn and at term. Electro-anatomo-clinical correlations

    Rev Electroencephalogr Neurophysiol Clin

    (1971)
  • G. Foffani et al.

    Reduced spike-timing reliability correlates with the emergence of fast ripples in the rat epileptic hippocampus

    Neuron

    (2007)
  • J. Glykys et al.

    Differences in cortical versus subcortical GABAergic signaling: a candidate mechanism of electroclinical uncoupling of neonatal seizures

    Neuron

    (2009)
  • M.S. Grubb et al.

    Abnormal functional organization in the dorsal lateral geniculate nucleus of mice lacking the beta 2 subunit of the nicotinic acetylcholine receptor

    Neuron

    (2003)
  • I. Khalilov et al.

    A novel in vitro preparation: the intact hippocampal formation

    Neuron

    (1997)
  • I. Khalilov et al.

    Epileptogenic Actions of GABA and Fast Oscillations in the Developing Hippocampus

    Neuron

    (2005)
  • R. Khazipov et al.

    Early patterns of electrical activity in the developing cerebral cortex of humans and rodents

    Trends Neurosci

    (2006)
  • J.C. Kreider et al.

    Mesopontine contribution to the expression of active 'twitch' sleep in decerebrate week-old rats

    Brain Res

    (2000)
  • M.D. Lamblin et al.

    Electroencephalography of the premature and term newborn. Maturational aspects and glossary

    Neurophysiol Clin

    (1999)
  • J.J. LoTurco et al.

    The multipolar stage and disruptions in neuronal migration

    Trends Neurosci

    (2006)
  • T. McLaughlin et al.

    Retinotopic map refinement requires spontaneous retinal waves during a brief critical period of development

    Neuron

    (2003)
  • H. Monyer et al.

    Developmental and regional expression in the rat brain and functional properties of four NMDA receptors

    Neuron

    (1994)
  • L. Nitecka et al.

    Maturation of kainic acid seizure-brain damage syndrome in the rat. II. Histopathological sequelae

    Neuroscience

    (1984)
  • M.J. O'Donovan

    The origin of spontaneous activity in developing networks of the vertebrate nervous system

    Curr Opin Neurobiol

    (1999)
  • H.F. Prechtl

    State of the art of a new functional assessment of the young nervous system. An early predictor of cerebral palsy

    Early Hum Dev

    (1997)
  • N.C. Spitzer

    Development of voltage-dependent and ligand-gated channels in excitable membranes

    Prog Brain Res

    (1994)
  • D. Stellwagen et al.

    An instructive role for retinal waves in the development of retinogeniculate connectivity

    Neuron

    (2002)
  • C.L. Torborg et al.

    Spontaneous patterned retinal activity and the refinement of retinal projections

    Prog Neurobiol

    (2005)
  • E. Tremblay et al.

    Maturation of kainic acid seizure-brain damage syndrome in the rat. I. Clinical, electrographic and metabolic observations

    Neuroscience

    (1984)
  • S. Vanhatalo et al.

    Development of neonatal EEG activity: From phenomenology to physiology

    Semin Fetal Neonatal Med

    (2006)
  • S. Vanhatalo et al.

    DC-EEG discloses prominent, very slow activity patterns during sleep in preterm infants

    Clin Neurophysiol

    (2002)
  • R.O. Wong et al.

    Transient period of correlated bursting activity during development of the mammalian retina

    Neuron

    (1993)
  • J.B. Ackman et al.

    Abnormal network activity in a targeted genetic model of human double cortex

    J Neurosci

    (2009)
  • J. Bai et al.

    RNAi reveals doublecortin is required for radial migration in rat neocortex

    Nat Neurosci

    (2003)
  • Y. Ben-Ari et al.

    GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations

    Physiol Rev

    (2007)
  • M.S. Blumberg et al.

    Dual mechanisms of twitching during sleep in neonatal rats

    Behav Neurosci

    (1994)
  • P. Bonifazi et al.

    GABAergic hub neurons orchestrate synchrony in developing hippocampal networks

    Science

    (2009)
  • C. Cepeda et al.

    Immature neurons and GABA networks may contribute to epileptogenesis in pediatric cortical dysplasia

    Epilepsia

    (2007)
  • A.R. Chandrasekaran et al.

    Evidence for an instructive role of retinal activity in retinotopic map refinement in the superior colliculus of the mouse

    J Neurosci

    (2005)
  • A.L. Chevassus et al.

    Abnormal connections in the malformed cortex of rats with prenatal treatment with methylazoxymethanol may support hyperexcitability

    Dev Neurosci

    (1999)
  • C. Chiu et al.

    Spontaneous activity in developing ferret visual cortex in vivo

    J Neurosci

    (2001)
  • I. Cohen et al.

    On the origin of interictal activity in human temporal lobe epilepsy in vitro

    Science

    (2002)
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