Biology subjects

Hertrich, N.

Publications and source records attributed to Hertrich, N..

5 recordsLinked to original sources

bioRxiv2026

Subtype-specific downregulation of voltage-gated sodium channels shapes neuronal responses to neuroinflammation

Epilepsy is one of the most common neurological disorders, affecting more than 50 million people worldwide. Among the genetic etiologies of epilepsy, variants in genes coding for ion channels are vastly represented and characterized. Notably, loss-of-function (LoF) mutations in voltage-gated sodium channels (NaV) genes can result in a wide range of phenotypes including West syndrome, autism spectrum disorder, or Dravet Syndrome. Although the implication of NaV subtypes in epileptic syndromes and the relationship between seizures and inflammation have been extensively described, subtype-specific neuronal responses to inflammation in the context of NaV loss-of-function remain poorly understood. In this study, we investigated the consequences of subtype-specific downregulation of NaV expression in primary mouse cortical neurons. Using shRNA-mediated silencing of Scn1a, Scn2a, or Scn8a, we generated neuronal cultures with reduced expression of NaV1.1, NaV1.2, or NaV1.6 and evaluated neuronal survival, inflammatory gene expression, and global transcriptomic responses under basal conditions and following an inflammatory challenge. Subtype-specific NaV downregulations did not produce a uniform phenotype. Rather, minor differences under basal conditions led to important discrepancies following exposure to an inflammatory stimulus. Notably, NaV1.1 reduction was associated with synaptic transcriptional changes, whereas NaV1.6 downregulation led to a substantial inflammatory signaling remodeling. Our observations suggest that the consequences of NaV dysfunction are not only determined by their role in neuronal excitability but also depend on subtype-specific responses to inflammatory cues. They notably shed light on the relevance of inflammatory events in the onset and progression of epileptic syndromes related to NaV loss-of-function mutations.

neuroscience↗

bioRxiv2025

Shaft versus spine localization affects the structural plasticity of glutamatergic synapses

In the early stages of development, most excitatory synapses are formed directly on dendritic shafts. As neurons mature, these sites gradually shift from the shaft to dendritic spines. In fully developed excitatory neurons, the majority of glutamatergic postsynaptic sites containing the postsynaptic density (PSD) molecules reside on dendritic spines. However, some glutamatergic synapses remain as shaft synapses, yet their characteristics have remained unexplored. Here, we show that the molecular composition of the shaft PSDs closely resembles that of spine PSDs. Key components such as AMPARs, NMDARs, CaV1.2 channels, and F-actin interacting proteins, SynGAP, as well as cortactin, are present in comparable amounts in both synapse types. The major distinction between shaft and spine PSDs lies in the lower abundance of the scaffold proteins Shanks and Homer in shaft PSDs. Shaft synapses are not merely passive structures but actively participate in synaptic transmission. Their structure and function are modulated by changes in neuronal activity. Long-term live imaging combined with a cLTP protocol revealed that shaft PSDs were potentiated but rarely underwent a transition to spine synapses. In contrast, during LTD, shaft PSDs were eliminated more frequently than their spine counterparts. Together, these findings highlight excitatory shaft synapses as a distinct, and notably less stable, synapse type.

neuroscience↗

bioRxiv2025

Dynamic regulation of neuronal Vault trafficking and RNA cargo by the noncoding RNA, Vaultrc5

Vaults are large ribonucleoprotein complexes of unknown function. Here, we report that the vault-associated noncoding RNA, Vaultrc5, is highly enriched at the synapse and is required for activity-dependent vault trafficking in primary cortical neurons. We have discovered that vaults are comprised of unique populations of coding and non-coding RNA, and that this cargo varies dynamically between subcellular compartments. In addition, Vaultrc5 knockdown at the synapse shifts the RNA cargo toward transcripts associated with immune surveillance, and Vaultrc5 knockdown, in vivo, leads to altered fear extinction learning. These findings suggest that the Vaultrc5 is critically involved in coordinating the experience-dependent trafficking of vaults and related RNA cargo, which may represent a novel feature of neuronal plasticity associated with learning and memory.

neuroscience↗

bioRxiv2024

Myosin VI controls localization of Golgi satellites at active presynaptic boutons

Neurons, as long-living non-dividing cells with complex morphology, depend on highly elaborate secretory trafficking system which ensures the constant delivery, removal and recycling of proteins and membranes. Previously, we have shown that simplified Golgi-related structures called Golgi satellites (GS), distinct from the somatic Golgi complex, are present in dendrites of primary hippocampal neurons and are involved in glycosylation and local forward trafficking of membrane proteins. However, whether GS are also targeted to axons of principal neurons have not been explored. Here, we investigate the subcellular distribution of GS in adult hippocampal neurons and discover that mobile and stationary GS are present along the entire axonal length, extending to the distal tips of the growth cone. Live imaging experiments revealed that neuronal firing modulates the switch between long range transport mediated by kinesin and dynein and stalling. We found that GS frequently pause or stop at pre-synaptic sites in activity-dependent manner. This behavior depends on the actin cytoskeleton and the actin-based motor protein myosin VI. Overall, our study demonstrates that neuronal activity can dynamically regulate the positioning of GS in the axon, shedding light on the intricate mechanisms underlying organelle trafficking in neurons. Significance statementOur study unveils the presence and dynamic behavior of Golgi satellites (GS), specialized organelles implicated in glycosylation and membrane protein trafficking, within axons of adult neurons. We found that mobile and stationary GS are present throughout the axonal length, including distal growth cone regions. GS are transported bidirectionally and their preferential pausing at presynaptic sites is regulated by neuronal firing. GS positioning at presynaptic boutons relies on the actin cytoskeleton and the myosin VI motor protein. This work elucidates how neuronal activity modulates GS distribution, shedding light on fundamental mechanisms of organelle trafficking in neurons.

neuroscience↗

bioRxiv2020

Synaptic anchoring of the endoplasmic reticulum depends on myosin V and caldendrin activity

Excitatory synapses of principal hippocampal neurons are frequently located on dendritic spines. The dynamic strengthening or weakening of individual inputs results in a great structural and molecular diversity of dendritic spines. Active spines with large Ca2+ transients are frequently invaded by a single protrusion from the endoplasmic reticulum (ER), which is dynamically transported into and out of spines by the actin-based motor myosin V. An increase in synaptic strength often correlates with stable anchoring of the ER, followed by the formation of the spine apparatus organelle. Here we show that synaptic ER stabilization depends on the interplay of two Ca2+-binding proteins: calmodulin serves as a light chain of myosin V and activates the motor function, whereas caldendrin acts as an inhibitor which transforms myosin into a stationary F-actin tether. Together, they provide a Ca2+-sensing module for fine-tuning myosin V activity and thereby regulate the formation of the spine apparatus in a subset of active dendritic spines.

neuroscience↗