Aleksandra BADURA The role of hind and midbrain inhibition in autism-like behaviours
IBENS Neuroscience seminar
11h à 12h30
Le séminaire d’Aleksandra BADURA (Erasmus Medical Center, Rotterdam) aura lieu dans la salle Favard, IBENS 46 rue d’Ulm 75005 Paris
Although our understanding of the molecular basis of brain development has advanced over the past decades, the function of many genes that regulate neuronal lineage-specification remains elusive. Recent work from my laboratory has uncovered a potential role for the transcription factor Pax5 and tumor suppressor Tsc1 in regulating the development of mid-brain and hind-brain GABAergic neurons and the role that they play in the development of behavioural deficits later in life.
Specifically, we showed that Pax5 mutant mice display behavioural deficits in all ASD domains similar to patients with PAX5 mutations. PAX5 deficiency also caused profound hypoplasia of the substantia nigra and ventral tegmental area due to loss of GABAergic neurons, thus affecting two midbrain hubs, controlling motor function and reward processing, respectively. Lineage tracing identified Pax5 as a crucial regulator of cerebellar morphogenesis and midbrain GABAergic neurogenesis. Our current studies show electrophysiological changes that are consistent with disinhibition of the midbrain dopaminergic system and a disbalance of excitation/inhibition in the midbrain.
We have also found that at early developmental stages Tsc1 haploinsufficiency leads to dysregulation of transcription factor Pax2. This dysregulation was accompanied by changes in the expression of mTOR pathway-related genes and downstream phosphorylation of S6. Our ongoing studies show that cerebellar inhibitory interneuron development is delayed in Tsc1 mutants compared to controls.
Together, these findings reveal new potential roles of Pax5 and Tsc1 in brain development and unravel the underlying mechanisms of neurodevelopmental delays.