16ème journée du Club Développement des Réseaux Neuronaux le 15 juin 2018




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Mutation of the α-tubulin Tuba1a leads to straighter microtubules and perturbs neuronal migration.

Brain development involves extensive migration of neurons. Microtubules (MTs) are key cellular effectors of neuronal displacement, which are assembled from α/β-tubulin heterodimers. Mutation of the α-tubulin isotype Tuba1a is associated with cortical malformations in humans. Belvindrah et al. (Team 2) provide detailed in vivo and in vitro analyses of Tuba1a mutants. In mice carrying a Tuba1a missense mutation (S140G), neurons accumulate and glial cells are dispersed along the rostral migratory stream (RMS) in postnatal and adult brains. Live-imaging of Tuba1a mutant neurons revealed slowed migration and increased neuronal branching, which correlated with directionality alterations and perturbed nucleus-centrosome (N-C) coupling. Tuba1a mutation led to increased straightness of newly polymerized MTs, and structural modeling data suggest a conformational change in the α/β- tubulin heterodimer. This work also shows that Tuba8, another α-tubulin isotype previously associated with cortical malformations, has altered function compared to Tuba1a. In resume, Tuba1a plays an essential, non-compensated role in neuronal saltatory migration in vivo, highlighting the importance of MT flexibility in N-C coupling and neuronal branching regulation during neuronal migration. (Belvindrah et al., J. Cell Biol., 2017).

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Early-born neurons are abnormally positioned in the doublecortin knockout hippocampus

Doublecortin knockout (Dcx KO) mice exhibit hippocampal epilepsy. Anatomically the hippocampus shows abnormally positioned neurons (heterotopia) and the mutant CA3 pyramidal layer is fragmented. Gene expression studies were performed by Khalaf-Nazzal, Stouffer et al (Team 2), using laser capture microdissection to separate the two Dcx KO CA3 neuronal layers (KO-I, KO-E), comparing these to the single layer in wild-type (WT) animals.
Comparing all KO cells to WT indicated serious cellular defects, pinpointed by cell stress, metabolism and organelle gene differences. Comparing the two Dcx KO layers between them, and individually to WT, revealed that they differ substantially from each other, and notably show differences in maturity at P0. Testing layer-specific genetic markers revealed a partial inversion of cells in the Dcx KO with normally deeper 'outer boundary' neurons being found superficially in the mutant (in KO-I). Outer boundary neurons are also the earliest-born and bromodeoxyuridine birthdating confirmed that these are abnormally positioned in the Dcx KO brain, with respect to all other neurons.
This work, identifying subpopulations of cells in the Dcx KO hippocampus, sheds light on key developmental mechanisms in this little-understood, curved structure. Perturbing anatomical position related to birthdate may contribute to hyperexcitability by affecting morphology and connectivity, cell stress and organelles. This is the first time to our knowledge that gene expression patterns have been used to distinguish the features of abnormally positioned neurons shedding light on their origins. Hum Mol Genet. 2016 Dec 22. pii: ddw370. doi: 10.1093/hmg/ddw370. [Epub ahead of print]

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GABAergic plasticity in the lateral habenula and cocaine withdrawal

Cocaine withdrawal can produce aversive states and vulnerability to relapse, both hallmarks of addiction. However, the neural circuits and molecular mechanisms underlying these aspects of withdrawal remain elusive. Frank J. Meye and Manuel Mameli show that cocaine withdrawal reduces the vesicular GABA transporter at synapses from pallidum to lateral habenula, thereby decreasing inhibitory transmission. These results, just published in the journal Nature Neuroscience, indicate that GABAergic synaptic plasticity within the lateral habenula is crucial for behaviors modeling cocaine-evoked aversive states and stress-induced relapse.

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