Biology subjects

Galkin, S.

Publications and source records attributed to Galkin, S..

4 recordsLinked to original sources

bioRxiv2025

m6A methylation regulates RNA axonal localisation and translation in developing neurons

Methylation on adenosine N6 (m6A) is an abundant post-transcriptional modification of the RNA that regulates almost the entire lifespan of RNA transcripts, from splicing and nuclear export to RNA stability and translation. Peripheral localisation of RNA is an event common to most cells and especially relevant in neurons where transcripts are trafficked to subcellular compartments to promote growth and differentiation in axons, and synaptic functions in dendrites. Here we show that in developing sympathetic neurons, m6A modification regulates RNA transport and local translation in axons. Critically, Nerve Growth Factor (NGF), a neurotrophin essential for axon growth and neuronal survival, promotes the axonal localisation of methylated transcripts and inhibits protein synthesis of trafficking RNAs, preventing premature protein expression. Noticeably, the translation of the bifunctional mRNA Trp53Inp2 depended on the methylation of the 3UTR, further supporting the key role of m6A modification in determining mRNA fate. Mutation of Trp53Inp2 m6A elements resulted in ectopic translation, defects of axon extension and neuronal death. Together, these data show that m6A is critical for RNA peripheral localisation and spatial regulation of protein expression.

neuroscience↗

bioRxiv2023

microRNA-218-5p Coordinates Scaling of Excitatory and Inhibitory Synapses during Homeostatic Synaptic Plasticity

Homeostatic synaptic plasticity (HSP) is a fundamental neuronal mechanism that allows networks to compensate for prolonged changes in activity by adjusting synaptic strength. This process is crucial for maintaining stable brain function and has been implicated in memory consolidation during sleep. While scaling of both excitatory and inhibitory synapses plays an important role during homeostatic synaptic plasticity, molecules coordinating both of these processes are unknown. In this study, we investigate the role of miR-218-5p as a regulator of inhibitory and excitatory synapses in the context of picrotoxin (PTX)-induced homeostatic synaptic downscaling (HSD) in rat hippocampal neurons. Using enrichment analysis of miRNA-binding sites in differentially expressed genes changing upon PTX-induced HSD, we bioinformatically predicted and experimentally validated increased miR-218-5p activity upon PTX-treatment in the process compartment. By monitoring synapse structure in vitro with confocal microscopy, we demonstrate that inhibiting miR-218-5p activity exerts a dual effect during HSD: it prevents the downscaling of excitatory synapses and dendritic spines, while at the same time blocking inhibitory synapse upscaling. Furthermore, we identify the Neuroligin2 interacting molecule Mdga1 as a crucial target of miR-218-5p in the context of homeostatic upscaling of inhibitory synapses. By performing long-term electroencephalographic (EEG) recordings, we further revealed that local inhibition of miR-218-5p in the somatosensory cortex reduced local slow-wave activity (SWA) during non-rapid-eye-movement (NREM) sleep. In summary, this study uncovers miR-218-5p as a key player in coordinating inhibitory and excitatory synapses during homeostatic plasticity and sleep. Our findings contribute to a deeper understanding of how neural circuits maintain stability in the face of activity-induced perturbations, with potential implications for both physiological and pathological conditions. Significance StatementHomeostatic synaptic plasticity mechanisms evolved to keep neuronal firing rates within a physiological range in response to alterations in neural network activity. It has been proposed that similar mechanisms take place during sleep in a process that promotes memory consolidation and synaptic renormalization. In this study, posttranscriptional regulation of synaptic proteins by miR-218-5p has been identified to coordinate both excitatory and inhibitory synaptic scaling during activity-dependent homeostatic synaptic plasticity. Intriguingly, local inhibition of miR-218-5p in the cortex of mice resulted in reduced slow-wave activity, an EEG-signature of synchronous firing during non-rapid eye movement sleep and a hallmark correlate of sleep pressure. Overall, these findings propose a convergent, posttranscriptional mechanism to coordinate both excitatory and inhibitory synaptic strength in response to alterations in neuronal activity with potential implications for sleep.

neuroscience↗

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↗

bioRxiv2018

Annelid Brain and Nerve Cord in Siboglinid Riftia pachyptila

Vestimentifera is a peculiar group of marine gutless siboglinids which has uncertain position in annelid tree. The detailed study of the fragmentary explored central nervous system of vestimentiferans and other siboglinids is requested to trace the evolution of the siboglinid group. Among all siboglinids the vestimentiferans preserve the gut rudiment what makes them a key group to homologize main cerebral structures with the ones of typical annelids, such as supra- and subesophageal commissures, cirsumesophageal connectives etc. Histologically we revealed main annelid brain structures in the compact large brain of Riftia pachyptila: circumesophageal connectives (longitudinal nerve tracts) and commissures (dorsal, supra- and subenteral commissures). Innervation of tentacles makes them homologous to peristomial palps of the rest annelids. The single nerve cord is represented by paired intraepidermal longitudinal strands associated with the ventral ciliary field in vestimentum and bearing giant axons originating from at least four pairs of perikarya. The absence of regularly positioned ganglia and lateral nerves in the nerve cord in vestimentum and trunk and presence of them in the opisthosome segments. Among siboglinids, the vestimentiferans distinguished by a large and significatly differentiated brain which is reflection of the high development of the palp apparatus. Osedax, frenulates and Sclerolinum have less developped brain. Frenulates and Sclerolinum have good ganglionization in the opisthosome, which probably indicates its high mobility. Comparative neuroanatomical analysis of the siboglinids and annelid sister clades allows us to hypothesize that the last common ancestor of siboglinids might had brain with a dorsal commissure giving rise neurite bundles to palps and paired ventral nerve cord.

zoology↗