Biology subjects

Hijazi, S.

Publications and source records attributed to Hijazi, S..

8 recordsLinked to original sources

bioRxiv2026

IsdH binding to hemoglobin:haptoglobin is decoupled from iron acquisition in Staphylococcus aureus

Staphylococcus aureus requires iron for proliferation during infection and acquires it mainly from host hemoglobin (Hb) through the iron-regulated surface determinant (Isd) system. The hemophores IsdB and IsdH mediate the initial steps of Hb recognition. Notably, IsdH also recognizes the hemoglobin:haptoglobin (HbHp) complex, although the molecular determinants and physiological relevance of this interaction remain unclear. Here, combining cryo-electron microscopy and biochemical and cellular assays, we define the basis of HbHp recognition by IsdH. The structure reveals how IsdH engages HbHp and captures the intrinsic conformational flexibility of the HbHp assembly. Functional analyses demonstrate that, despite retaining the ability to extract heme from HbHp, IsdH does not support S. aureus growth under iron-restricted conditions when HbHp is the sole iron source. These findings suggest that HbHp recognition by IsdH may serve functions beyond nutrient iron acquisition, contributing to modulation of host-pathogen interactions.

biochemistry↗

bioRxiv2025

Granularity of thalamic head direction cells

Head direction signaling is fundamental for spatial orientation and navigation. The anterodorsal nucleus of the thalamus (ADn) contains a high density of head direction (HD) cells that process sensorimotor inputs for subsequent synaptic integration in postsynaptic cortical areas. We tested the hypothesis that individual HD cells show differences in their firing patterns and connectivity by recording and juxtacellularly labeling single HD cells in subregions of the ADn in awake mice during passive rotation. We identified HD cells that exhibited different response profiles to light, sound, and movement. We also identified a mediolateral gradient of calretinin-expressing (CR+) ADn cells, with CR+ HD cells having narrower tuning widths, lower maximal firing rates, and different intrinsic properties compared to CR-cells. Axons of labeled HD cells could be followed to the retrosplenial cortex, with collaterals innervating the thalamic reticular nucleus (type I cells); others additionally innervated the dorsomedial striatum (type II cells). Most medial CR+ cells preferentially projected to ventral retrohippocampal regions. Surprisingly, we also identified a subpopulation of medial CR+ cells with twisted dendrites and descending axons that avoided the thalamic reticular nucleus, termed tortuosa HD cells (type III cells). We conclude that HD cells of the mouse ADn comprise distinct cell types, providing parallel head-direction-modulated sensorimotor messages to synaptic target neurons within the head direction network.

neuroscience↗

bioRxiv2025

Two birds with one stone: a novel potential antibiotic blocking IsdB-mediated heme extraction by Staphylococcus aureus with serendipitous hemoglobin left-shifting activity

Infections caused by Staphylococcus aureus are closely linked to its ability to secure essential nutrients, including iron, which is extracted from the heme of human hemoglobin (Hb) through the iron-regulated surface determinant (Isd) system. The compound 4-[[2-[[5- (1H-indol-3-yl)-1,3,4-oxadiazol-2-yl]sulfanyl]acetyl]amino]benzoate (C35) was recently identified as a new potential antimicrobial agent for its ability to bind Hb and hamper its interaction with the staphylococcal hemophore IsdB in vitro. Here, we show that C35 inhibits S. aureus growth by specifically targeting the hemophore-driven iron acquisition system. Our findings confirm both the potential of C35 as a first-in-class protein-protein interaction inhibitor with antimicrobial activity, and the effectiveness of targeting hemophores as a strategy to inhibit S. aureus growth. To gain information for drug discovery purposes, the X-ray structure of Hb in the presence of the compound was solved. Unexpectedly, we discovered that, rather than the predicted binding pose, the molecule binds to tetrameric Hb in a cleft between the alpha subunits, stabilizing an R2 relaxed Hb conformation. This triggered further investigation of the effect of C35 on Hb functional properties, which showed a pronounced left-shift activity on oxygen binding curve (i.e., it strongly increases the Hb oxygen affinity). These results highlight C35 as a promising dual-acting compound with both antimicrobial activity and the ability to modulate Hb function through non-covalent stabilization of a high-affinity state. Author SummaryStaphylococcus aureus is a dangerous bacterium that can cause severe infections in humans. To grow and survive it needs iron, which it steals from our red blood cells by taking it from hemoglobin, the protein that carries oxygen in the blood. In this study, we focused on a small molecule, called C35, that blocks the interaction between hemoglobin and a key bacterial protein involved in heme acquisition. We found that C35 strongly inhibits the growth of S. aureus when hemoglobin is the only available source of iron, showing a potential new method to starve the pathogen and consequently fight the infection. Surprisingly, we also found that C35 increases the affinity of hemoglobin for oxygen. This dual action makes C35 a unique molecule for future therapeutic development, with potential applications both as a new antimicrobial agent and in the treatment of diseases related to hemoglobin function.

microbiology↗

bioRxiv2024

Pathological tau alters head direction signaling and induces spatial disorientation

Spatial disorientation, an early symptom of dementia, is emerging as an early and reliable cognitive biomarker predicting future memory problems associated with Alzheimers disease, but the underlying neural mechanisms have yet to be fully defined. The anterodorsal thalamic nucleus (ADn) exhibits early and selective vulnerability to pathological misfolded forms of tau, a major hallmark of Alzheimers disease and ageing. The ADn contains a high density of head direction (HD) cells, which contribute to spatial navigation and orientation. Hence, their disruption may contribute to spatial disorientation. To test this, we virally expressed human mutant tau (htau) in the ADn of adult mice. HD-tau mice were defined by phosphorylated and oligomeric forms of htau in ADn somata and in axon terminals in postsynaptic target regions. Compared to controls, HD-tau mice exhibited increased looping behavior during spatial learning, and made a greater number of head turns during memory recall, indicative of spatial disorientation. Using in vivo extracellular recordings, we identified htau-expressing ADn cells and found a lower proportion of HD cells in the ADn from HD-tau mice, along with reduced directionality and altered burst firing. These findings provide evidence that expression of pathological human tau can alter HD signaling, leading to impairments in spatial orientation.

neuroscience↗

bioRxiv2023

A minimum threshold for myelination of pyramidal cells in human and mouse neocortex

Neocortical pyramidal neurons are frequently myelinated. Diversity in the topography of axonal myelination in the cerebral cortex has been attributed to a combination of electrophysiological activity, axonal morphology, and neuronal-glial interactions. Previously, we showed that axonal segment length and calibre are critical determinants of fast-spiking interneuron myelination (Stedehouder, J. et al (2019). However, the factors that determine the myelination of individual axonal segments along neocortical pyramidal neurons remain largely unexplored. Here, we used structured illumination microscopy and cell type-specific manipulations to examine the extent to which axonal morphology determines the topography of axonal myelination in mouse neocortical pyramidal neurons. We found that, unlike what was determined for fast-spiking interneurons, the joint combination of axonal calibre and interbranch distance does not predict axonal myelination in pyramidal neurons, rather it provides a minimum threshold for myelination; pyramidal neurons with an axon calibre and interbranch distance lower than 0.24 {micro}m and 19 {micro}m, respectively, are almost never myelinated. Moreover, we further confirmed that these findings in mice also extend to human neocortical pyramidal cell myelination, suggesting that this mechanism is evolutionarily conserved. Taken together, our findings suggest that axonal morphology is highly deterministic of the topography and cell-type specificity of neocortical myelination.

neuroscience↗

bioRxiv2023

Dysfunctional parvalbumin interneurons in a genetic mouse model of schizophrenia

The 22q11 deletion syndrome (22q11DS) is an interstitial microdeletion associated to an increased risk of developing schizophrenia. In this disorder, there is a dysfunction in the overall connectivity of the brain. Parvalbumin-expressing (PV+) interneurons have been associated with multiple pre- and post-synaptic impairments that affect various brain regions. Specifically, previous results have suggested that alterations in hippocampal networks may be related to PV+ interneurons dysfunction. In this study, we used the Df1 mouse model that carries the 22q11 deletion to examine the excitability of PV+ cells in the dorsal CA1 region of the hippocampus, due to its importance in memory and cognition. We found that PV+ interneurons were hyperexcitable in this region. To understand the source of the altered excitability, we measured potassium currents, highly involved in the intrinsic firing properties of neurons. We observed that voltage-gated potassium channel subfamily A member 1 (Kv1.1) was impaired in PV+ cells. Specific activation of this channel recovered some of the excitability disturbances observed in Df1 mice. Furthermore, blockade of synaptic inputs also restored PV+ interneurons excitability. Taken together, these results suggest that PV excitability is increased in the CA1 region of the hippocampus and it is partially mediated by Kv1.1 in a mouse model of 22q11DS.

neuroscience↗

bioRxiv2023

A critical period for prefrontal cortex PV interneuron myelination and maturation

AbstractRecent studies have highlighted axonal myelination as a common feature of parvalbumin-positive (PV) interneurons throughout the cerebral cortex. However, the precise function of PV interneuron myelination remains incompletely understood. In this study, we used the cuprizone model of demyelination to investigate how PV interneuron myelination might influence their neuronal physiology. Specifically, we examined whether impairing myelination from postnatal day 21 onwards, during a critical neurodevelopmental period of the prefrontal cortex (PFC), can affect PV interneuron maturation and function. Using whole-cell patch-clamp recordings to examine intrinsic properties of PV interneurons in the PFC, we found that juvenile demyelination induced robust alterations of PV interneuron firing patterns. Specifically, we observed that demyelination caused an impairment in the ability of PV interneurons to sustain high frequency firing associated with a substantial decrease in Kv3-specific currents. We also found a significant impairment in PV interneuron autaptic self-inhibitory transmission, a feature implicated in temporal control of PV interneuron firing during cortical network activity. Following a remyelination period of 5 weeks, PV interneuron properties were only partially recovered and mice showed clear social deficits, suggesting that transient juvenile demyelination leads to long-lasting behavioral impairments. In contrast, adult demyelination had no significant effects on PV interneuron firing properties. Together, our data uncovers a critical period for juvenile myelination as an important factor in PFC PV interneuron development and brain maturation.

neuroscience↗

bioRxiv2022

Rapid specification of human pluripotent stem cells to functional astrocytes

Astrocytes are essential for the formation and maintenance of neural networks through metabolic support, facilitation of synaptic function, and optimization of electrophysiological activity. However, a major technical challenge for investigating astrocyte function and disease-related pathophysiology has been the limited ability to obtain functional human astrocytes. Here we present a novel method to efficiently differentiate human pluripotent stem cell (hPSC)-derived neural progenitors to functional astrocytes in 28 days using a culture medium containing leukemia inhibitory factor (LIF) and bone morphogenetic protein 4 (BMP4). This approach yields highly pure populations of astrocytes expressing canonical astrocyte markers, which we confirmed by immunofluorescence, flow cytometry and RNA sequencing. Human PSC-derived astrocytes efficiently buffer glutamate and robustly support neural network activity. Co-cultures of hPSC-derived astrocytes and neurons on multi-electrode arrays generated robust network activity within 2 days and synchronous network bursts after 6 days. Whole cell patch-clamp recordings revealed an increased frequency of postsynaptic currents in human hPSC-derived neurons co-cultured with hPSC-derived versus primary rodent astrocytes, consistent with a corresponding increase in synapse density. Furthermore, hPSC-derived astrocytes retained their hominid morphology when transplanted into a mouse brain. In conclusion, we present a novel protocol to obtain functional astrocytes from human pluripotent stem cells, providing a platform for investigating human astrocyte function and neuronal-glial interactions.

neuroscience↗