Biology subjects

Kalavai, S. V.

Publications and source records attributed to Kalavai, S. V..

6 recordsLinked to original sources

bioRxiv2026

Astrocytes instructively regulate neuronal translation

Neuronal protein synthesis is essential for synaptic plasticity and long-term memory, yet whether its regulation is shaped by other cell types remains poorly understood. Here, we show that astrocyte-secreted proteins regulate global neuronal translation depending on astrocytic state. Astrocyte-conditioned medium (ACM) increased neuronal translation under basal conditions, an effect enhanced by astrocyte stimulation with the activity-dependent factor BDNF, whereas ACM from neurotoxic reactive astrocytes, a state linked to neuroinflammation and Alzheimers disease, suppressed neuronal translation. Across these conditions, neuronal mTORC1 activity consistently tracked with translational output, whereas the integrated stress response (ISR) acted through distinct, state-specific mechanisms that did not always track with neuronal translation. Furthermore, we identified astrocyte-secreted apolipoprotein E (APOE) and its associated cargo as a negative regulator of neuronal translation that contributed to the decreased translation induced by neurotoxic reactive astrocytes. We also found that astrocyte-secreted signals required neuronal endocytosis to influence translation and drove synaptic remodeling dependent on glutamatergic signaling and neuronal mTORC1 activity. Together, these findings identify astrocytes as active, instructive regulators of neuronal translation and synaptic structure, with implications for understanding how astrocyte dysfunction may disrupt the translational mechanisms underlying impairments in synaptic plasticity and long-term memory in neurodegenerative disease. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/741020v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@74ecborg.highwire.dtl.DTLVardef@1c620a0org.highwire.dtl.DTLVardef@881b8corg.highwire.dtl.DTLVardef@1c8b7e4_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Entorhinal Cortex Wolframin-1-expressing neurons propagate tau to CA1 neurons and impair hippocampal memory

Tau pathology emerges early in Alzheimers disease within entorhinal cortex layer II (ECII) and reaches hippocampal CA1, but how this circuit-level spread translates into sex-dependent vulnerability remains unclear. Using a circuit-defined model in which P301L human tau is expressed selectively in Wolframin-1 (Wfs1+) ECII neurons and propagates to CA1, we found that the extent and proximal-distal distribution of tau-positive CA1 neurons were comparable in males and females. Despite similar propagation, females exhibited broad hippocampal-dependent cognitive impairment (working memory, object recognition, fear acquisition, trace associative memory, and contextual fear memory), whereas males showed a selective deficit in trace associative memory. Consistent with these behavioral outcomes, CA1 pyramidal neurons in tau-propagated females displayed reduced excitability (slower action potential kinetics, reduced firing during depolarizing steps) and reduced spontaneous excitatory postsynaptic current (EPSC) amplitude, while males showed subtler intrinsic changes with altered EPSC kinetics. Bulk RNA sequencing of entorhinal cortex and CA1 revealed robust immune pathway engagement after tau propagation, with males showing a stronger Th1/Th2 and neuroinflammatory signature and CTLA4-associated signaling changes, whereas females showed prominent complement-phagosome pathway enrichment and a female-specific increase in Clec7a+ microglia density in CA1. CD4+ T-cell infiltration into CA1 was detected in both sexes. Together, these results indicate that sex-specific neuroimmune programs, rather than differences in tau propagation load, shape CA1 electrophysiological dysfunction and the breadth of memory impairment following early entorhinal-to-hippocampal tau spread.

neuroscience↗

bioRxiv2026

Tau-induced ribosomal collisions impair memory through the activation of the integrated stress response

The formation of new long-term memories is reliant upon the spatial and temporal regulation of mRNA translation. Translational control has been demonstrated to be disrupted in neurodegenerative diseases, which exhibit impairments in both homeostatic translation and memory formation, such as Alzheimers disease (AD) and frontotemporal dementia (FTD). However, the precise mechanisms by which this dysregulation occurs, as well as the pathogenic consequences of this dysregulation have yet to be described. Here we establish that FTD-associated tau mutations impair protein synthesis prior to the onset of memory impairments by slowing ribosomal elongation speed, causing ribosomes to collide upon mRNAs. We reveal that this tau-induced ribosomal collision ultimately impairs memory-associated translation through activation of the integrated stress response (ISR) via GCN2. Pharmacological prevention of this ISR activation not only rescues memory formation in the PS19 mouse model of FTD, but also attenuates neuronal death, decreases tau phosphorylation and accumulation, and improves survival. Collectively, our data elucidates a novel mechanism by which mRNA translation is impaired early in neurodegeneration, identifies several pathological phenotypes which are traceable to impairments in mRNA translation, and highlights the therapeutic potential of rescuing these translational impairments.

neuroscience↗

bioRxiv2025

Sex specific correction of maternal inflammation-induced behavioral abnormalities by the inhibition of colony-stimulating factor 1 receptor

We have previously reported the therapeutic effect of depletion and regeneration of endogenous microglia on autism spectrum disorder-like behaviors in offspring from the dams under maternal immune activation (MIA) by dampening their neuritogenic activation. Here we show a long-lasting pathological effect by MIA, leading to abnormal behaviors in offspring mice in a sex-specific manner at 3 months of age. MIA was induced by injecting Polyinosinic:polycytidylic acid [Poly(I:C)] at 10mg/kg at E9.5 with preselected dams based on the immunoreactivity to low-dose Poly(I:C) injection. MIA offspring show impairments in sociability, repetitive behavior, and spatial working and associative memories in both sexes, whereas only male offspring show social novelty deficit. MIA has no effect on anxiety-like behavior nor sensori-motor or locomotor activity. Administering colony stimulating factor receptor (CSF1R) inhibitor in young adult MIA offspring regenerates microglia and ameliorates sociability deficits in males and spatial working and associative memory impairments in both sexes without effect on social novelty impairments. Transcriptomic analysis of prefrontal cortex and hippocampal tissues reveals MIA and sex-specific pathways and highlights potential key genes involved in the corrective effect of microglial regeneration in MIA offspring. Our results underscore the potential of the sex-specific therapeutic applications of CSF1R inhibitor for MIA-related social and cognitive disorders.

animal behavior and cognition↗

bioRxiv2025

Mapping the spatiotemporal dynamics of de novo protein synthesis during long-term memory formation

The formation of new associative long-term memory (LTM) following Pavlovian conditioning is dependent upon multiple, temporally distinct windows of mRNA translation. Current methods lack the temporal specificity to robustly characterize the dynamics of protein synthesis throughout the rodent brain following conditioning. Here we resolve these technological limitations and demonstrate that in awake mice, the retro-orbital (RO) injection of azidohomoalanine (AHA) enables the labelling and subsequent visualization of the brain de novo proteome, with labelling periods as short as 30 minutes. Combining this advancement in de novo proteomic labelling with tissue clearing, we identified brain region, cell-type, and neuronal sub-population specific changes in de novo protein synthesis in mice following an auditory threat conditioning paradigm. This approach also allowed us to track the changes in de novo protein synthesis over time, revealing that conditioning-induced changes in mRNA translation exhibit remarkable temporal specificity in brain regions such as the somatosensory cortex. Taken together, our findings highlight how this novel labelling technique can be used to map the highly intricate temporal and spatial dynamics of mRNA translation after behavioral conditioning.

neuroscience↗

bioRxiv2020

Elucidating the pathogenic mechanisms of AD brain-derived tau-containing extracellular vesicles: Highly transmissible and preferential propagation to GABAergic neurons

Extracellular vesicles (EVs) propagate tau pathology for Alzheimers disease (AD). How EV transmission influences AD are, nonetheless, poorly understood. To these ends, the physicochemical and molecular structure-function relationships of human brain-derived EVs, from AD and prodromal AD (pAD), were compared to non-demented controls (CTRL). AD EVs were shown to be significantly enriched in epitope-specific tau oligomers versus pAD or CTRL EVs assayed by dot-blot and atomic force microscopy tests. AD EVs were efficiently internalized by murine cortical neurons and transferred tau with higher aggregation potency than pAD and CTRL EVs. Strikingly, inoculation of tau-containing AD EVs into the outer molecular layer of the dentate gyrus induced tau propagation throughout the hippocampus. This was seen in 22 months-old C57BL/6 mice at 4.5 months post-injection by semiquantitative brain-wide immunohistochemistry tests with multiple anti-phospho-tau (p-tau) antibodies. Inoculation of the equal amount of tau from CTRL EVs or as oligomer or fibril-enriched fraction from the same AD donor showed little propagation. AD EVs induced tau accumulation in the hippocampus as oligomers or sarkosyl-insoluble proteins. Unexpectedly, p-tau cells were mostly GAD67+ GABAergic neurons and to a lesser extent, GluR2/3+ excitatory mossy cells, showing preferential EV-mediated GABAergic neuronal tau propagation. Whole-cell patch clamp recording of Cornu Ammonis (CA1) pyramidal cells showed significant reduction in the amplitude of spontaneous inhibitory post-synaptic currents. This was accompanied by reductions in c-fos+ GAD67+GABAergic neurons and GAD67+ GABAergic neuronal puncta surrounding pyramidal neurons in the CA1 region confirming reduced interneuronal projections. Our study posits a novel tau-associated pathological mechanism for brain-derived EVs.

neuroscience↗