Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.10.21.760639

Endogenous retrovirus activation disrupts postsynaptic organization in human glutamatergic neurons

Davis-Hansson, C.·Garza, R.·Piochon, C.·Johansson, J. G.·Busskamp, V.·Jakobsson, J.·Johansson, E. M.
View original source ↗Export metadata ↓

Abstract

Endogenous retroviruses (ERVs) comprise a substantial fraction of the human genome, yet whether their expression can directly alter human neuronal function remains unknown. Because glutamatergic signaling is fundamental to brain function and frequently disrupted in brain disorders, we asked whether activation of the primate-specific ERV-W group, associated with neurological disease, perturbs human glutamatergic neurons. We used CRISPR activation of the LTR17-ERV-W consensus sequence to examine its effects on neuronal and synaptic function, inducing transcription from multiple proviral loci, including five with intact open reading frames. Functionally, ERV-W activation selectively altered the postsynaptic compartment, reducing PSD-95 and NMDA receptor abundance. These changes were accompanied by altered excitatory synaptic transmission and reduced intrinsic excitability, whereas activation of ERVW-1/Syncytin-1 alone did not reproduce the phenotype. Our findings identify ERV-W activation as a modulator of human neuronal function with potential relevance to ERV-associated brain disorders.

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Davis-Hansson, C., Garza, R., Piochon, C., Johansson, J. G., Busskamp, V., Jakobsson, J., Johansson, E. M.. 2026-10-23. Endogenous retrovirus activation disrupts postsynaptic organization in human glutamatergic neurons. https://doi.org/10.64898/2026.10.21.760639

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

KEEP EXPLORING

Related preprints

bioRxiv2026

Brain representations of visual short-term memories during healthy human aging: occipital decline and frontoparietal compensation

Visual short-term memory declines steeply with age, but the link to neural representations of memory content remains unknown. We used fMRI decoding to relate remembered motion-direction representations in visual and frontoparietal cortex to age and performance, in 115 adults, aged 25-87, from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) cohort. Decoding was strongest in visual cortex, but also significant in frontoparietal regions, with different profiles. Visual representations weakened with memory load and age, and statistically mediated age-related performance decline, especially during recall. This coupling, however, weakened with age: some older adults retained stronger visual representations than performance implied, suggesting impaired access to a partially preserved memory trace. Frontoparietal representations, instead, were largely insensitive to load and strengthened with age during maintenance, partially offsetting performance decline. Therefore, interventions to boost VSTM in older adults might target compensatory frontoparietal representations during memory maintenance, and readout of untapped visual representations at recall.

neuroscience↗
bioRxiv2026

Lexical surprisal drives pupil dilation during continuous story listening

The pupil famously adjusts its dilation in response to light, but its role extends far beyond this basic sensory function. Its fluctuations index arousal and mental effort, beyond luminance-related dynamics, making it a sensitive marker of internal cognitive states. A growing body of work shows that these pupil-linked signals extend beyond the visual domain. However, which processes drive pupil responses in more naturalistic settings remains unclear as most evidence comes from tightly controlled paradigms that strip away the richness of real-world experience. Language offers a uniquely powerful window into this question, as it can allow us to create rich paradigms without having any visual, i.e. luminance, confounds. Moreover, language comprehension hinges on continuous prediction: listeners constantly generate expectations about upcoming input, and the discrepancy between expectation and actual input - contextual prediction error, or surprisal - carries measurable cognitive costs. Here, we tested the hypothesis that pupil-linked arousal indexes these linguistic surprisal signals during naturalistic listening. We recorded pupil responses while volunteers listened to naturalistic spoken stories in darkness, which were either intact or reversed. Reversed speech preserves the acoustics of the signal while destroying its intelligibility. Pupil dilation selectively tracked lexical surprisal within a late window of 1,700 to 2,350 milliseconds following word onset, in forward, but not control, backward speech. These findings indicate that pupil-linked arousal is tuned to global, context-dependent processing, tracking the cognitive cost of updating a predictive model during naturalistic listening.

neuroscience↗
bioRxiv2026

Disrupting SORL1-retromer endosomal recycling in mice drives the age-dependent neurodegenerative signature of Alzheimer's disease

MRI studies have mapped the atrophic signature that distinguishes Alzheimer's disease (AD), isolating regions differentially vulnerable to its age-dependent neurodegenerative process. We test the hypothesis that an endosomal recycling pathway regulated by the interaction of SORL1 with retromer, which is pathogenically disrupted in AD, might drive the neurodegenerative process via multiple yearlong studies in over 140 wildtype and SORL1 deficient mice, modeling AD's causative mutations. MRI studies revealed that SORL1 deficiency induced an age-dependent AD-pattern of atrophy, centered on the trans-entorhinal cortex, and that atrophy was prevented by SORL1 restoration, secondary to overexpressing the retromer protein VPS26b. Postmortem studies validated that the atrophy reflects neuronal loss. Proteomic profiling revealed that the atrophy is associated with reductions in cell death suppressors, one of which was then found deficient in the trans-entorhinal cortex of AD patients. Besides supporting the hypothesis, taken together with other findings, the results suggest that SORL1-retromer disruptions represent a therapeutically-amenable common 'neurodegeneration pathway' in AD.

neuroscience↗