Developmental basis of seizure susceptibility: a focus on dopaminergic and serotonergic systems

The embryonic development of the Central Nervous System (CNS) requires an orchestrated series of events tightly regulating the patterning and regionalization of the neural tube, as well as the proliferation, survival and differentiation of distinct neuronal populations. All these events are controlled by cascades of activation of transcription factors that regulate the expression of specific subsets of genes in restricted regions and neuronal populations of the developing CNS. Among these transcription factors, homeobox-containing proteins play a crucial role, and altered expression of these factors can impact embryonic as well as adult CNS functions. In particular, homeobox-containing genes have been described to crucially regulate differentiation of dopaminergic and serotonergic neurons during brain development. Dopaminergic and serotonergic neurons, respectively located in midbrain and hindbrain regions, diffusely innervate several forebrain areas, contributing to regulate several physiological functions including brain excitability. Classical pharmacological studies clearly showed that both dopamine and serotonin markedly regulate seizure susceptibility through specific receptor pathways. Our recent studies, performed on classical and conditional knockout mouse lines, demonstrate that altered embryonic development of dopaminergic and serotonergic neurons results in altered seizure susceptibility in the adult life. Here we will review our major findings, in light of other studies recently published by other groups.