Biology subjects

Salter, E. W.

Publications and source records attributed to Salter, E. W..

5 recordsLinked to original sources

bioRxiv2026

Emergence of microglia structural and functional heterogeneity between hippocampal subregions during development into early adulthood

Phagocytosis is a key function performed by microglia to maintain tissue homeostasis. The degree of microglial phagocytic activity differs across ages and between gross anatomical brain regions, dictated by the local environment. Here, we asked whether microglial phagocytic phenotype exhibits subregion-scale tuning by circuit-specific features within a brain region. To address this, we took advantage of the highly stereotyped architecture of the hippocampus. We examined three adjacent synaptic subregions, the CA1 stratum radiatum (SR), stratum lacunosum moleculare (SLM) and dentate gyrus molecular layer (DGML). These three subregions provide an ideal system for examining local microglia heterogeneity, as each subregion contains distinct neuropil features, creating three adjacent unique micro-environments to which the microglia are exposed. We measured the phagocytic activity and morphological properties of over 1,000 individual microglia at two developmental points, mid-postnatal (P16) and early adulthood (P60) in the CA1 SR, SLM and DGML. We found that microglial phenotype diversified with development into early adulthood. At the mid-postnatal age, phagocytic activity and morphology were homogeneous across subregions. Conversely, in young adulthood, microglia in the CA1 SR and DGML exhibited a reduction in phagocytic activity, while microglia in the CA1 SLM maintained a highly phagocytic phenotype reminiscent of an immature-like state. These findings uncover a fine-scale tuning of microglia activity that emerges during maturation and is dictated at the sub-region level of the hippocampus, uncovering a distinct population of microglia in the CA1 SLM that exhibit a persistent immature phenotype under physiological conditions. Understanding the target(s) of this phagocytosis and consequences for CA1 SLM function will provide new insight into the role of local tuning of microglia properties for circuit-specific needs in both health and disease.

neuroscience↗

bioRxiv2025

Tau deletion results in sex-dependent modulation of synaptic weakening in rat hippocampus

Tangles, a defining characteristic of Alzheimers disease (AD), are composed principally of hyperphosphorylated and misfolded tau species. However, dysregulation of tau precedes tangle formation by many years and is associated with cognitive decline, the best functional correlate of which is synaptic weakening and eventual synaptic loss. Although tau is present at synapses, its normal synaptic function is poorly understood - information vital to the rational development of tau-modifying therapies. Since rats have a greater cognitive repertoire than mice and display more robust signs of tau pathology in AD models, we developed a tau knockout (Mapt-/-) rat to investigate the impact of tau elimination on synaptic function. We observed that long-term depression (LTD), a form of synaptic weakening, is enhanced in the hippocampus of male, but not female, rats. This enhanced LTD was dependent on the synaptic activation of group I metabotropic glutamate receptors and involved altered synaptic actin polymerization. These studies therefore provide mechanistic insights into how tau modulates synaptic function via regulation of the actin cytoskeleton. Our findings are relevant to the understanding of the physiological roles of synaptic tau, the functional consequences of tau-lowering therapies, and the influence of sex in AD susceptibility.

neuroscience↗

bioRxiv2023

Chronic pain mediated changes in the appetitive value of affective touch in mice

The existence of skin-to-brain circuits for rewarding gentle touch highlight its critical nature across species. However, this gentle affective touch is not always appetitive and can produce aversion or negative affect in disorders such as chronic pain. Sensory neurons expressing the protein MrgprB4 detect gentle stroking in mice and their activation of these neurons known to be positively reinforcing. Here we assess whether activation of channelrhodopsin (ChR2) expressing MrgprB4 afferents signal positively valenced tactile information and whether this is altered in models of chronic pain. We further interrogate how this this sensory information is reflected in the downstream circuits recruited. Optogenetic activation of MrgprB4 lineage afferents was found to be appetitive in control and capsaicin sensitized mice but not nerve injured mice, indicating that the appetitive value is diminished in neuropathic pain. Remarkably, this appetitive value was partially recovered in male nerve injured mice by treatment with the analgesic gabapentin. These behavioral changes were also accompanied by different patterns of neuronal activity throughout the brain, including altered activation of sites that receive direct projections from the spinal cord between sham and nerve injured mice. Together, these findings highlight the plastic nature of these affective tactile circuits under pathological conditions.

neuroscience↗

bioRxiv2022

Amyloid-β1-42 oligomers enhance mGlu5R-dependent synaptic weakening via NMDAR activation and complement C3aR/C5aR signaling

Synaptic dysfunction, weakening, and loss of synapses are well-correlated with the pathology of Alzheimers disease (AD). Oligomeric amyloid beta (oA{beta}) is considered a major synaptotoxic trigger for AD. Recent studies have implicated hyperactivation of the complement cascade as the driving force for loss of synapses caused by oA{beta}. However, the initial synaptic cues that trigger pathological complement activity remain elusive. Here, we examined a form of synaptic long-term depression (LTD) mediated by metabotropic glutamate receptors (mGluR) which is disrupted in rodent models of AD. Exogenous application of oA{beta} (1-42) to mouse hippocampal slices enhanced the magnitude of mGlu subtype 5 receptor (mGlu5R)-dependent LTD. We found that the enhanced synaptic weakening occurred via both NMDARs and complement C3aR/C5aR signaling. Our findings reveal a mechanistic interaction between mGlu5R, NMDARs, and the complement cascade in synaptic weakening induced by oA{beta}, which could represent an early trigger of synaptic loss and degeneration in AD.

neuroscience↗

bioRxiv2020

Complement C3-dependent glutamatergic synapse elimination in the developing hippocampus is region- and synapse-specific

Withdrawal statementThe authors have withdrawn their manuscript owing to the results of this pre-print being based on experiments performed prior to COVID-19 shutdowns, which required a near complete culling of the mouse colony. Upon re-initiating the colony, the phenotype outlined in the pre-print could no longer be observed and as such we have decided to withdraw the pre-print. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

neuroscience↗