Aurore Thomazeau, doctor in neurosciences at the University of Bordeaux, was one of the winners of the Jérôme Lejeune young researcher’s award. She answers our questions.
What was the subject of your thesis, what was your starting point and what were your interrogations?
My thesis project, which was directed by Dr. Olivier Manzoni, in close collaboration with Dr. Jean Dellabar, aimed at studying the mechanisms of prefrontal synaptic mechanisms in Down Syndrome murine models (T21) which have an additional copy of the Dyrk1a gene.
Because it codes for an enzyme involved in development control and neuronal functioning, Dyrka1a gene, present on the chromosome, is suspected to be one of the major causes for intellectual disability in people with Down Syndrome. My work aims at determining what are the consequences of the overexpression of the Dyrk1a gene on neuronal activity within the prefrontal cortex(PFC) which is a key structure involved in the complex behavioural response which intervenes in most abstract intellectual tasks.
Neurons communicate with each other within a specialized zone called Synapse. It is made of a presynaptic part, belonging to the neurons in the higher part and of a postsynaptic part, or dendritic spine for excitatory synapses, belonging to the neurons in the lower part.
The first objective of this work has been to evaluate in mice, which were genetically modified so that they had an extra copy of the Dyrk1a gene, the excitatory synaptic transmission of the principal neurons in the PFC, as well as other synaptic parameters such as the density of the dendritic spine and the quantity of synaptic proteins involved in excitatory transmission.
What did your research on the implication of DYRK1A enable you to discover ?
The evaluation of the synaptic transmission was carried out thanks to neuronal electrophysiological recordings of parts of mice’s brains containing the PFC. A portrait of the electric activity within the PFC was drawn (intrinsic properties of the neurons, basal properties of synapses and the capacities of the synapses to modulate their activity (synaptic plasticity). Tridimensional reconstruction of the morphology of neurons, drawn up from high resolution images obtained thanks to confocal microscopy, enabled to evaluate the density of their dendritic spines. Biochemical analysis by western blot enabled to quantify synaptic proteins.
This work enabled to put into evidence that the overexpression of the Dyrk1a gene alters the plasticity of the PFC synapses. What’s more, we have managed to show that this loss of “synaptic flexibility” was associated to an excess of dendritic spines and a decrease of an active form of a protein, CaMKII, involved in synaptic reinforcement (long term potentiation).
In parallel, you elaborated therapeutic strategies: what did you discover and what results did you obtain?
Intervening directly on the activity of the enzyme thanks to a natural inhibitor, EGCG, which is the main polyphenol in green tea, is an interesting lead to counterbalancing the overexpression of the gene. This pharmacologic approach could reduce the effects of the overexpression of the Dyrk1a gene on neuronal activity.
Based on the precedent work of Dr. Jean Delabar’s team, a second part of the study consisted in evaluating the effects of a treatment, with green tea extracts rich in EGCG diluted in drinking water, on adult mice whose Dyrk1a genes were overexpressing. The idea was to check its effect on PFC synaptic transmission.
We discovered that this EGCG treatment on mice enabled to recuperate some kind of synaptic plasticity as well as recuperating affected synaptic parameters
What are your short and medium term perspectives, brought up by your research, for the years to come?
Apart from the information delivered on the physiological implication of the Dyrk1a protein in the synaptic function, our work is fitted in a translational research programme with a greater objective, aiming at identifying new therapeutic targets (in this case the Dyrk1a protein) which could enabled, at first, to ameliorate the life conditions of patients carriers of Down Syndrome (in this case by amelioration their intellectual capabilities). These results, combined with those of Dr. Jean Delabar (2009 Guedj), issued from research on murine models are to be viewed in parallel with the clinical trials led by Dr. Mara Dierssen’s team in Barcelona
How do you see your future for the years to come?
I will be joining Dr. Mark Bear’s team at the Picower Institute for Learning and Memory at Cambridge, next May. I will focus on studying synapses in murine models in genetic intellectual diseases other than Down Syndrome. I will be studying Fragile-X as well as the various forms of autism spectrum disorder. I would also like to have closer relations with the clinical field.
If you had one, what would your end of career dream be?
HA hA! The 2013 physiology Nobel Prize was awarded, last October, to Thomas Sudhof, amongst others. I know him thanks to his work on the cycles of synaptic vesicles. Is “nobelization” the researcher’s ultimate consecration?
Giving my contribution to improve knowledge of this black box which is our grey matter, by having asked myself the right questions, finding the best adapted technical means to efficiently answer those questions and transmit what I have learnt would be fully satisfying. And, anyway, does a researcher’s career ever, really, come to an end?