Biology subjects

Salgado, M.

Publications and source records attributed to Salgado, M..

4 recordsLinked to original sources

bioRxiv2026

Environmental risk reshapes high-confidence schizophrenia risk genes during a developmental window of vulnerability

Rare coding variants and environmental exposures such as early-life stress contribute to schizophrenia risk, but whether environmental adversity alters the expression of genetically implicated genes remains unclear. Combining the limited bedding and nesting (LBN) model of early-life stress (ELS) with 24-plex single-cell mFISH registered to the Allen Mouse Brain Atlas, we profiled the ten genes identified in the original SCHEMA study, the complement gene C4b and activity markers in 1.29 million cells across four postnatal ages. Whole-brain risk-gene upregulation was greatest at postnatal day 21 (P21), with region- and cell-type-selective effects that prominently involved the hypothalamus. Sp4 and Cacna1g showed distinct temporal responses: Sp4 increased at P21 and decreased at P90 in hypothalamic oligodendrocytes, whereas Cacna1g decreased at P10. ELS-associated C4b upregulation extended across neuronal and glial populations, including oligodendrocytes and OPCs. Across regional cell types, P10 C4b effects were positively correlated with P21 Grin2a effects. These findings suggest that ELS perturbs the developmental expression of genes implicated in schizophrenia, identifying potential molecular links between environmental adversity and genetic vulnerability.

neuroscience↗

bioRxiv2026

Humanized FLT3 mice display enhanced tissue engraftment and support HIV-1 persistence and rebound

Despite advances in antiretroviral therapy (ART), HIV-1 cure efforts remain hindered by viral reservoirs in long-lived myeloid cells and immune-privileged tissues that are less accessible and therefore unlikely to be assessed in human clinical trials. Consequently, there is a critical need for robust research platforms such as immune cell humanized mice to bridge preclinical and clinical HIV research. However, previously described humanized mouse models have demonstrated incomplete hematopoietic development, particularly showing low levels of NK or myeloid cells. Herein, we present the novel humanized FLT3 mouse model that develops NK cells, myeloid progenitors, monocytes, and both functional conventional (cDCs) and plasmacytoid dendritic cells (pDCs) to support HIV-1 infection. Human cord blood derived CD34+ hematopoietic stem cells (HSC) were engrafted in the FLT3 (Hu-FLT3) and NSG (Hu-NSG) mouse strains for comparison. Our data showed that while Hu-NSG and Hu-FLT3 mice have comparable human lymphocyte levels, the proportion of myeloid cells (including monocytes, pDCs and cDCs) in Hu-FLT3 mice (16.2 %) was three-fold higher than in Hu-NSG mice (5.6 %) and the proportion of NK cells was six-fold higher (12.8 % and 1.9 %, respectively). Both strains successfully supported HIV-1 infection, maintain viral replication for 17 weeks in untreated mice, and proviral DNA was detectable in peripheral blood, bone marrow and spleen. While ART effectively reduced viral load to undetectable levels in four weeks in both strains, we observed viral rebound after treatment discontinuation within 3 weeks, reaching the same levels of viral load pre-ART and mimicking what is observed in people living with HIV (PLWH).Human immune cells and HIV-1 RNA were higher in tissues of Hu-FLT3 mice compared to Hu-NSG mice, mirroring features reported in human tissue reservoirs. Our findings demonstrated that Hu-FLT3 mice support enhanced development of human innate immune cells in blood and tissues, which are associated with higher levels of HIV-1 replication compared to Hu-NSG mice. This study establishes a novel, robust and accessible in vivo platform to investigate potential HIV cure and persistence-targeting interventions with translational relevance to human therapeutic development thanks to the improved and more complete human immune repertoire in Hu-FLT3.

immunology↗

bioRxiv2024

Overexpression of the schizophrenia risk gene C4 in PV cells drives sex-dependent behavioral deficits and circuit dysfunction.

Fast-spiking parvalbumin (PV)-positive cells are key players in orchestrating pyramidal neuron activity, and their dysfunction is consistently observed in myriad brain diseases. To understand how immune complement dysregulation - a prevalent locus of brain disease etiology - in PV cells may drive disease pathogenesis, we have developed a transgenic mouse line that permits cell-type specific overexpression of the schizophrenia-associated complement component 4 (C4) gene. We found that overexpression of mouse C4 (mC4) in PV cells causes sex-specific behavioral alterations and concomitant deficits in synaptic connectivity and excitability of PV cells of the prefrontal cortex. Using a computational network, we demonstrated that these microcircuit deficits led to hyperactivity and disrupted neural communication. Finally, pan-neuronal overexpression of mC4 failed to evoke the same deficits in behavior as PV-specific mC4 overexpression, suggesting that C4 perturbations in fast-spiking neurons are more harmful to brain function than pan-neuronal alterations. Together, these results provide a causative link between C4 and the vulnerability of PV cells in brain disease.

neuroscience↗

bioRxiv2023

C4 induces pathological synaptic loss by impairing AMPAR trafficking.

During development, activation of the complement pathway, an extracellular proteolytic cascade, results in microglia-dependent synaptic elimination via complement receptor 3 (CR3). Here, we report that decreased connectivity caused by overexpression of C4 (C4-OE), a schizophrenia-associated gene, is CR3 independent. Instead, C4-OE triggers GluR1 degradation through an intracellular mechanism involving endosomal trafficking protein SNX27, resulting in pathological synaptic loss. Moreover, the connectivity deficits associated with C4-OE were rescued by increasing levels of SNX27, linking excessive complement activity to an intracellular endolysosomal recycling pathway affecting synapses.

neuroscience↗