Chapter 45 - The developing cortex
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
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2021, Neurochemistry InternationalCitation Excerpt :In FCD many of the cytomegalic dysmorphic neurons display immature markers (Palmini et al., 2004). Failure of maturation of neurons and presence of mal-developed synaptic circuits demonstrate epileptic activity (Ben et al., 2013). This work was conducted on tissue samples collected from patients, both FCD type I (n = 14) and FCD type II (n = 16), undergoing resection surgery for drug resistant FCD.
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2020, Cell ReportsCitation Excerpt :Further studies are needed to determine whether the difference in GABAergic presynapses between neurons with or without microglial association is through preventing new synapses and/or promoting synapse stripping by microglia. Since GABAergic synapses are formed before glutamatergic ones in the cortex and intracellular Clā ion levels are intrinsically high at this early stage of brain development (Wang and Kriegstein, 2008), GABA provides most of the excitatory drive during this immature period and may therefore contribute positively to seizure generation (Ben-Ari, 2013; Dzhala and Staley, 2003; Glykys et al., 2009) (Figures S4EāS4G). Infants, rather than adults, may be more prone to FSs because of the depolarization, but not hyperpolarization, of GABAās action in the cortex and hippocampus at this age (Chung, 2014; Kong et al., 2019).
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