Basic developmental rules and their implications for epilepsy in the immature brain.

The construction of the human brain with its 10(15) synapses follows a set of complex developmentally and environmentally regulated steps. A series of sequences have been described that are instrumental, in the sense that a failure of any one of them leads to dramatic, life-long consequences. Hence the importance of determining the sequential maturation of neurons, synapses and cortical maps. It is also important to determine how network-driven events become installed, as neuronal activity intervenes in all of these steps and modulates, for better or worse, the outcome. A fundamental consequence of these sequential events is that any disruption will have very different consequences depending on when it occurs, indeed, "when is as important as what". An obvious aspect of these general features is related to seizures. In fact, the developing brain has both a higher incidence of seizures in human and animal models, and experiences seizures that can produce long-lasting consequences that are also stage-dependent. This seminar and the series of slides presented are an introduction to these issues, summing up several studies made notably by INMED researchers during the last two decades (http://www.inmednet.com). It concentrates on four basic developmental rules: i) the generation by very immature neurons, of very large currents mediated by the activation of receptors in neurons that bear no synapses. This is due to the release of GABA that diffuses to distal sites and acts as a paracrine factor; ii) the excitatory/inhibitory shift of the actions of GABA during development because of a progressive reduction in the intracellular chloride concentration; iii) the sequential formation of GABAergic synapses and networks before glutamatergic ones, implying that, at an early stage, all the excitatory drive will be GABAergic; iv) the presence, at an early stage, of a unique, primitive pattern in all developing structures, this pattern disappears when most GABAergic synapses have shifted to their adult configuration. Several consequences of these sequences are described including: i) a control of neuronal migration by GABA-acting drugs, and the possibility that migration disorders are also generated by environmental factors that include the effects of GABA-acting agents; ii) If GABA excites immature neurons and inhibits adult one, then GABA-acting agents will also produce different effects on the mother and the embryo; iii) early brain oscillations are generated by the periphery and propagate centrally - notably to the sensory-motor cortex, suggesting that peripherally-generated movements may provide an important signal for the formation of cortical maps, in keeping with the importance of embryonic movements; iv) "seizures beget seizures" in the developing brain. This has now been shown in a triple chamber with the two intact hippocampi that we developed, and with which it has been possible to show that only recurrent seizures that include high frequency oscillations can transform the naïve, contralateral hippocampus to an epileptic one that seizes spontaneously. Most interestingly, at an early developmental stage, when GABA excites many neurons and the density of glutamatergic synapses is not sufficiently high, purely glutamatergic seizures cannot lead to long-term consequences, the additional excitatory drive provided by GABAergic synapses is needed. In other words, at that stage, blocking GABA synapses generates seizures, as in adults, but these do not lead to long-term consequences. The mechanisms that underlie these differences is due to the need for high frequency oscillations (> 80 Hz or so), and these can only be generated when GABA synapses are operative in the developing brain: GABA receptor antagonists are ictogenic, but not epileptogenic. To facilitate teaching purposes the paper is published together with supplemental data (as a PowerPoint presentation included in the accompanying DVD), thus allowing an overview of important developmental steps and their implications.