Dendritic excitation–inhibition balance shapes cerebellar output during motor behaviour

Feedforward excitatory and inhibitory circuits regulate cerebellar output, but how these circuits interact to shape the somatodendritic excitability of Purkinje cells during motor behaviour remains unresolved. Here we perform dendritic and somatic patch-clamp recordings in vivo combined with optogenetic silencing of interneurons to investigate how dendritic excitation and inhibition generates bidirectional (that is, increased or decreased) Purkinje cell output during self-paced locomotion. We find that granule cells generate a sustained depolarization of Purkinje cell dendrites during movement, which is counterbalanced by variable levels of feedforward inhibition from local interneurons. Subtle differences in the dendritic excitation–inhibition balance generate robust, bidirectional changes in simple spike (SSp) output. Disrupting this balance by selectively silencing molecular layer interneurons results in unidirectional firing rate changes, increased SSp regularity and disrupted locomotor behaviour. Our findings provide a mechanistic understanding of how feedforward excitatory and inhibitory circuits shape Purkinje cell output during motor behaviour

A novel protein kinase D phosphorylation site in the tumor suppressor Rab interactor 1 is critical for coordination of cell migration

RIN1 is a regulator of epithelial cell migration. We identify serine 292 as a novel phosphorylation site for PKD in RIN1. Phosphorylation at this site controls RIN1-mediated inhibition of cell migration by modulating the direct activation of Abl kinases

The tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition

Nearly half of the human genome is made of transposable elements (TEs) whose activity continues to impact its structure and function. Among them, Long INterspersed Element class 1 (LINE-1 or L1) elements are the only autonomously active TEs in humans. L1s are expressed and mobilized in different cancers, generating mutagenic insertions that could affect tumor malignancy. Tumor suppressor microRNAs are ∼22nt RNAs that post-transcriptionally regulate oncogene expression and are frequently downregulated in cancer. Here we explore whether they also influence L1 mobilization. We show that downregulation of let-7 correlates with accumulation of L1 insertions in human lung cancer. Furthermore, we demonstrate that let-7 binds to the L1 mRNA and impairs the translation of the second L1-encoded protein, ORF2p, reducing its mobilization. Overall, our data reveals that let-7, one of the most relevant microRNAs, maintains somatic genome integrity by restricting L1 retrotransposition.European Research Council (ERC) ERC-2009-StG 243312French National Research Agency (ANR) ANR-11-LABX-0028-01 ANR-15-IDEX-01Centre National de la Recherche Scientifique (CNRS) 3546University Hospital Federation (FHU) OncoAgeMINECO PEJ-2014-A-31985 SAF2015-71589-PMINECO by European Regional Development Fund SAF2015-71589-PSpanish Government RYC-2016-21395Career Integration Grant-Marie Curie FP7-PEOPLE-2011-CIG-30381