Objective
Our two main goals are to determine in the two mouse models briefly described below:
which effectors mediate the deleterious effect of serotonin on cortical development, and
whether developmental defects are involved in the adult behavioural syndrome.
Using genetic, histochemical, electrophysiological and behavioural approaches, we will study in mutant mice (and in normal rodents with or without drugs affecting the serotonergic system):
the geometry and development of thalamocortical axons;
the role of serotonin in the maturation of cortical neurons;
the trophic effects of serotonin in primary cultures of cortical and thalamic neurons;
the expression of neurotrophins and their receptors in the cortex and thalamus;
the transient expression of aminergic transporters and receptors in thalamic neurons;
the role of serotonin receptors in serotonin's suppressive effect on the barrelfield development;
the generality of absence of barrelfield in MAOA deficiency - effect of the genetic background;
the functional consequences of altered somatosensory cortex in adult plasticity;
the effect of an excess of serotonin on neonatal thalamocortical transmission;
the development of the visual cortex and subcortical thalamic and tectal relays;
the adult behaviour after inhibition of serotonin synthesis during development - aggression.
Finally, we will determine:
the expression pattern of serotonin receptors and transporters in the cortex and thalamus of primate foetuses;
how to best explore cortical defects in MAOA-deficient men, depending on the findings in the mouse models and on the possibility of recruiting human cases to clinical trials.
The project is historically based on the recent discovery of the psychiatric syndrome of monoamine oxidase A (MAOA) deficiency by a Dutch group, and on four original sets of data obtained in mice by three laboratories involved in the project. Men who lack MAOA, the main degradative enzyme for serotonin, display enhanced aggression and borderline mental retardation; and (i) mice of a strain knockout for MAOA display enhanced aggression and a disrupted cytoarchitecture in the somatosensory barrel cortex; (ii) such a lack of barrelfield is also a characteristic of another type of mutant mice, the BRL mouse strain, with the critical brl locus being located on chromosome 11, whereas the MAOA gene is on the X chromosome; (iii) early treatment of MAOA-deficient or BRL mouse pups with the inhibitor of serotonin synthesis parachlorophenylalanine restores barrelfield development; and (iv) surprisingly, glutamatergic thalamocortical afferents to sensory cortices in normal rodents express the specific serotonin transporter during development.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences neurobiology
- natural sciences mathematics pure mathematics geometry
- natural sciences biological sciences genetics chromosomes
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Coordinator
91405 Orsay
France
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