Trends in Neurosciences
Volume 31, Issue 12, December 2008, Pages 626-636
Journal home page for Trends in Neurosciences

Review
Neuro-archaeology: pre-symptomatic architecture and signature of neurological disorders

https://doi.org/10.1016/j.tins.2008.09.002Get rights and content

During brain development cells divide, differentiate and migrate to their assigned targets to form synapses and active cell assemblies. This sequence is controlled both by genetic programs and environmental factors. Alterations of this sequence by mutations or environmental insults leads to the formation of misconnected circuits endowed with a ‘pre-symptomatic signature’. I propose here that early- and late-onset neurological disorders as diverse as infantile epilepsies, mental retardation, dyslexia or, in certain conditions, even Huntington’s and Alzheimer’s disease might be, in part, born at early developmental stages before symptoms appear. The core of this working hypothesis is that imaging or non-invasive recordings might unravel signatures of disorders to come, thereby permitting earlier diagnosis and potential treatment of neurological disorders.

Section snippets

The developing brain is talkative but uses a different language to adults

In contrast to one widely held assumption, no developmental stage is fully automated and even undifferentiated cells are not mute. Rather, they are endowed from the earliest developmental stages with functional communication strategies (Figure 1). Contrary to the construction of a machine, for example, the brain is active during its construction. It must generate the appropriate cellular and network patterns that provide the signals needed for development, while avoiding an imbalance between

The developing and adult brains respond differently to environmental insults

Because several processes including proliferation or migration occur primarily in the developing but not the adult brain, it comes as no surprise that a wide range of agents and procedures produce brain malformations in the former but not the latter. For example, in utero administration of the anti-mitotic agent methyl-azoxy-methanol leads to the formation of small heterotopic masses and an aberrant functional bridge between the neocortex and hippocampus 63, 64, 65, 66. Cocaine, alcohol and

Genetic mutations are talkative during development

Many mutations identified in relation to infantile epilepsies, mental retardation and dyslexia are due to disruption of proteins that are essential for synapse operation, receptor-mediated signalling, transporters, cytoskeleton proteins and other processes 94, 95, 96. It has been suggested that mental retardation unassociated with apparent structural abnormalities has a delayed phenotype because mutations of proteins that are essential for synaptic activity and plasticity are not needed at

In utero disruption of genes linked to early disorders leads to subtle malformations

Knockout and knock-in strategies have contributed to the study of gene functions but have some inherent limitations owing to compensatory mechanisms and redundancy of essential processes that can result in no phenotype, a lethal one or one that does not mimic the human pathology. Cell-specific and developmental-stage-dependent inactivation of proteins alleviates these limitations and enables identification of the underlying neuronal population in which the proteins are disrupted. A recently

Time and space dependence of the effects of mutations: a ‘programmed response to insults’?

Things are, however, more complex because genes have divergent roles at various developmental stages and within different brain structures. Thus, a mutation of the sushi SRPX2 gene leads to perisylvian polymigrogyria indicating an early developmental function, but another mutation of the same gene leads to a syndrome with verbal dyspraxia but no apparent brain malformation 132, 133. It is possible that, like other sushi domain proteins (the drosophila hikaru genki), SRPX2 also plays a part in

Acknowledgements

I am heavily endebted to P. Szepetowski, O. Dulac, G.H. Holmes, R. Guerrini, N. Spitzer and C. Cardoso for their insights and criticism of the review and to J. Asmanis for secretarial assistance. Financial support for my work has been provided by INSERM (www.inserm.fr), Fondation pour la Recherche Médicale (www.frm.org), Fédération pour la Recherche sur le Cerveau (www.frc.asso.fr) and l’Agence Nationale de la Recherche (www.agence-nationale-recherche.fr).

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