The anticonvulsant and mood-stabilizing drug valproic acid attracts C. elegans and activates chemosensory neurons via a cGMP signaling pathway

Rogel-Hernandez, L. E.; Casademunt, H.; Samuel, A. D. T.; Goodman, M. B.

doi:10.1101/2025.11.11.687732

Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.11.11.687732

The anticonvulsant and mood-stabilizing drug valproic acid attracts C. elegans and activates chemosensory neurons via a cGMP signaling pathway

Rogel-Hernandez, L. E.·Casademunt, H.·Samuel, A. D. T.·Goodman, M. B.

View original source ↗Export metadata ↓

Abstract

Valproic acid (VPA) is a drug with both anticonvulsant and antimanic properties. It has been widely prescribed to treat epilepsy, bipolar disorder, and other neuropsychiatric conditions for decades, but prenatal exposure is linked to developmental anomalies, cognitive deficits, and an increased risk of autism. Remarkably, the molecular basis of VPA action in the brain is not fully understood. To determine VPAs effect on the nervous system without requiring systemic drug application that induce toxic effects, we exploited the well-characterized chemotaxis behavior of the nematode Caenorhabditis elegans. We found that C. elegans are attracted to VPA, and this behavior is missing in animals lacking the tax-4 ion channel and the tax-4-expressing AWC chemosensory neurons. To test the idea that VPA directly activates the AWC neurons, we performed calcium imaging studies in a line expressing GCaMP6s in all amphid chemosensory neurons in the head. We found that VPA evoked calcium transients consistently in the AWC neurons and variably in AWB and ASH. As cyclic nucleotide-gated channels, the active state of tax-4 increases upon the binding of cGMP. Within the worms chemosensory nervous system, receptor guanylate cyclases (rGCs) facilitate the synthesis of cGMP and serve as chemoreceptors for various chemical cues. By performing chemotaxis assays and calcium imaging experiments with rGC mutants against VPA, we found that odr-1 and gcy-28 are essential for mediating VPA attraction, as their absence disrupts both behavior and control AWC calcium transients. However, given their broad use in chemosensation, odr-1 and gcy-28 most likely act as downstream effectors rather than as direct targets. These findings compelled us to investigate whether chemoreceptors belonging to the G protein-coupled receptor (GPCR) family contribute to VPA sensing. We approached this hypothesis by conducting chemotaxis assays with G mutants and identified several (odr-3, egl-30, gpa-2;gpa-3) whose absence leads to a loss of VPA attraction. Thus, future studies should focus on elucidating the mechanisms by which GPCRs contribute to VPA sensing and cGMP signaling.

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Rogel-Hernandez, L. E., Casademunt, H., Samuel, A. D. T., Goodman, M. B.. 2025-11-12. The anticonvulsant and mood-stabilizing drug valproic acid attracts C. elegans and activates chemosensory neurons via a cGMP signaling pathway. https://doi.org/10.1101/2025.11.11.687732

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

A systems-level model of sleep-dependent memory-consolidation failure in neurodegeneration: the spindle-slow-oscillation decoupling cascade dissociates amyloid and tau

During non-rapid-eye-movement (NREM) sleep, the temporal coupling of cortical slow oscillations (SOs), thalamic spindles, and hippocampal sharp wave ripples drives the consolidation of declarative memories. This coupling degrades in ageing and Alzheimers disease (AD), and although A{beta} and tau leave dissociable signatures in human sleep, the mechanisms by which progressive pathology dismantles the consolidation machinery are difficult to isolate experimentally, and have not to our knowledge been reproduced in a model that can be perturbed directly. We built a systems-level model in which cortical SOs and thalamic spindles are generated by reduced oscillators, hippocampal ripples replay encoded spike sequences, and the measured per-event SO-spindle timing alignment causally gates spike-timing dependent plasticity on cortical sequence synapses. A post-sleep cued-recall test reads out consolidation. Five neurodegeneration parameters (amyloid, tau, synaptic density, GABAergic inhibition, cholinergic tone) map to dis tinct mechanisms grounded in the human and animal literature. The model reproduces graded healthy consolidation and a progressive collapse in which coupling, slow-wave power, spindle power and recall fall monotonically and the overnight memory effect flips from consolidation to net forgetting, with weak memories failing first. Scrambling SO-spindle timing while holding oscillation power fixed abolishes consolidation, establishing that coupling timing, rather than oscillation power, is what the plasticity gate depends on within the model. A{beta} and tau impair memory through orthogonal signatures (A{beta} collapses slow-wave power while sparing replay order, tau the reverse) and this orthogonality holds across the entire A{beta} x tau plane and survives simultaneous {+/-}50% resampling of every mapping coefficient (40/40 samples), so it is not an artefact of a single calibration point. The model yields a falsifiable clinical prediction: closed-loop slow-oscillation enhancement rescues memory only when the deficit is amplitude/coupling-dominated, not when it is replay(tau)-dominated, despite normalising slow-wave power in both cases. Because the therapy arms dissociate coupling from memory benefit, the model also cautions against adopting SO-spindle coupling as a standalone surrogate endpoint.

neuroscience↗

bioRxiv2026

Toxicity of MAPT 4R RNA Contributes to Motor Neuron Degeneration in ALS

MAPT (Tau) dysregulation is implicated in several neurodegenerative diseases, but its contribution to amyotrophic lateral sclerosis (ALS) is poorly understood. Here we show that mRNA isoforms encoding 4-repeat (4R) Tau are upregulated and cytoplasmically enriched in iPSC-derived motor neurons (MNs) from VCP-mutant and sporadic ALS, without a corresponding change in Tau protein. Using splice-switching antisense oligonucleotides and isoform-specific siRNAs, we find that enhanced 4R expression reduces MN viability, whereas its selective knockdown improves survival, with kinetics more consistent with an RNA-intrinsic effect than altered protein synthesis. Exon 10-containing MAPT RNA shows increased predicted secondary structure, self-association and altered Tau biocondensation in vitro. In post-mortem ALS cervical spinal cord, increased relative exon 10 usage is associated with a higher-risk clinical phenotype and shorter disease duration These findings identify an isoform-specific contribution of MAPT to MN vulnerability in ALS and nominate 4R MAPT RNA as a therapeutic target.

neuroscience↗

bioRxiv2026

30 Hz High-Definition Transcranial Alternating Current Stimulation at the Left Frontal Cortex Reduces the Spectral Slope of the EEG in the Contralateral Hemisphere

Background: High-definition transcranial alternating current stimulation (HD-tACS) is favored by the neurostimulation community for its precision and ability to influence neuronal dynamics. Yet, the exact mechanism by which the underlying brain structures are being affected remains unclear. We believe that the investigation of the aperiodic nature of the electroencephalograph (EEG) could shed light on the modulatory effects of HD-tACS. Methods: We analyzed the EEG of 9 participants during a compensatory tracking task (CTT) in two sessions, each with different HD-tACS protocols. Every session consisted of an initial period of no stimulation, followed by 30 Hz HD-tACS in the left motor (M30) or frontal (F30) cortex. We then isolated the aperiodic component of the EEG and calculated its spectral slope {beta}. Results and Discussion: {beta} decreased during F30 mainly in the right frontal cortex, indicating a shift towards higher frequencies and an increase of the excitatory/inhibitory balance. Additionally, we found that despite the long monotonus task the accuracy of the participants did not decrease, which might be attributed to the ability of both M30 and F30 to sustain attention for prolonged time. Finally, the change of CTT accuracy during the stimulation correlated with the {beta} of specific channels before the stimulation. This indicates the potential of {beta} to be used as a screening biomarker in future studies. In conclusion, we showed the ability of HD-tACS to alter EEG aperiodic dynamics and paved the way for future exploration of such dynamics in the field.

neuroscience↗