Biology subjects

Soutschek, M.

Publications and source records attributed to Soutschek, M..

4 recordsLinked to original sources

bioRxiv2023

A human-specific microRNA controls the timing of excitatory synaptogenesis

Neural circuit development in the human cortex is considerably prolonged in comparison to non-human primates, a trait that contributes to the remarkable cognitive capacity of modern humans. Here, we explore the regulatory role of non-coding RNAs, which dramatically expanded during brain evolution, in synapse development of human-induced pluripotent stem-cell derived neurons. We found that inhibition of a human-specific microRNA, miR-1229-3p, alters the trajectory of human neuronal maturation and enhances excitatory synaptic transmission. Transcriptome analysis following miR-1229 knockdown revealed a downregulation of mitochondrial DNA (mtDNA) encoded genes. We further show that miR-1229 regulates mitochondrial morphology, mtDNA abundance and matrix calcium concentration, and that stimulation of mitochondrial metabolism rescues decreased calcium buffering in miR-1229-3p depleted neurons. Accordingly, miR-1229 directly targets an entire network of genes involved in mitochondrial function and ER-associated protein homeostasis. Our findings reveal an important function of human-specific miR-1229-3p in developmental timing of human synaptogenesis and generally implicate non-coding RNAs in the control of human connectivity and cognition. One-Sentence SummaryA human-specific microRNA slows down the formation and maturation of neuronal synapses by reducing mitochondrial metabolism.

neuroscience↗

bioRxiv2021

scanMiR: a biochemically-based toolkit for versatile and efficient microRNA target prediction

microRNAs are important post-transcriptional regulators of gene expression, but the identification of functionally relevant targets is still challenging. Recent research has shown improved prediction of microRNA-mediated repression using a biochemical model combined with empirically-derived k-mer affinity predictions. Here, we translate this approach into a flexible and user-friendly bioconductor package, scanMiR, also available through a web interface. Using lightweight linear models, scanMiR efficiently scans for binding sites, estimates their affinity, and predicts aggregated transcript repression. Moreover, flexible 3-supplementary alignment enables the prediction of unconventional interactions, such as bindings potentially leading to target-directed microRNA degradation (TDMD) or slicing. We showcase scanMiR through a systematic scan for such unconventional sites on neuronal transcripts, including lncRNAs and circRNAs.

bioinformatics↗

bioRxiv2021

microRNA-138 controls hippocampal interneuron function and short-term memory

The proper development and function of neuronal circuits relies on a tightly regulated balance between excitatory and inhibitory (E/I) synaptic transmission, and disrupting this balance can cause neurodevelopmental disorders, e.g. schizophrenia. microRNA-dependent gene regulation in pyramidal neurons is important for excitatory synaptic function and cognition, but its role in inhibitory interneurons is poorly understood. Here, we identify miR-138-5p as a regulator of short-term memory and inhibitory synaptic transmission in the hippocampus. Sponge-mediated miR-138-5p inactivation specifically in parvalbumin (PV)-expressing interneurons impairs spatial recognition memory and enhances GABAergic synaptic input onto pyramidal neurons. Cellular and behavioural phenotypes associated with miR-138-5p inactivation are paralleled by an upregulation of the schizophrenia-associated Erbb4, which we validated as a direct miR-138-5p target gene. Our findings suggest that miR-138-5p is a critical regulator of PV interneuron function, with implications for cognition and schizophrenia. More generally, they provide evidence that microRNAs orchestrate neural circuit development by fine-tuning both excitatory and inhibitory synaptic transmission.

neuroscience↗

bioRxiv2020

Pervasive compartment-specific regulation of gene expression during homeostatic synaptic scaling

Synaptic scaling is a form of homeostatic plasticity which allows neurons to adjust their action potential firing rate in response to chronic alterations in neural activity. Synaptic scaling requires profound changes in gene expression, but the relative contribution of local and cell-wide mechanisms is controversial. Here we performed a comprehensive multi-omics characterization of the somatic and process compartments of primary rat hippocampal neurons during synaptic scaling. Thereby, we uncovered both highly compartment-specific and correlated changes in the neuronal transcriptome and proteome. Whereas downregulation of crucial regulators of neuronal excitability occurred primarily in the somatic compartment, structural components of excitatory postsynapses were mostly downregulated in processes. Motif analysis further suggests an important role for trans-acting post-transcriptional regulators, including RNA-binding proteins and microRNAs, in the local regulation of the corresponding mRNAs. Altogether, our study indicates that compartmentalized gene expression changes are widespread in synaptic scaling and might co-exist with neuron-wide mechanisms to allow synaptic computation and homeostasis.

neuroscience↗