Trends in Neurosciences
ReviewNeuro-archaeology: pre-symptomatic architecture and signature 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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2020, Biological PsychiatryCitation Excerpt :We found a perturbation of USV calls without alterations in motor behavior. First, our results revealed that GABA exhibits excitatory properties in the mPFC in early development before transitioning to inhibition between P10 and P15, as ascertained by cell-attached recordings, in line with the timing of this transition in other regions of the developing rat brain, including the hippocampus (37,41), cerebellum (38), and neocortex (76). This maturational trajectory is mediated by a change in GABArev, ascertained by single-channel recordings of GABA-mediated Cl− currents.