Biology subjects

Abraham, W. C.

Publications and source records attributed to Abraham, W. C..

8 recordsLinked to original sources

bioRxiv2026

Synaptic plasticity deficits via aberrant engagement of metaplasticity in the hippocampus of PS19 mice

Tauopathy is characterized by progressive synaptic failure and neuroinflammation, yet the laminar-specific nature of these disruptions remains poorly understood. We investigated hippocampal functional integrity and glial reactivity in 8-10-month-old PS19 (P301S) mice. Electrophysiological recordings in the CA1 stratum radiatum revealed an unexpected increase in basal synaptic transmission despite profound deficits in both maintenance and early induction of the LTP phase. Conversely, the dentate gyrus exhibited reduced basal transmission and impaired LTP maintenance, alongside significant paired-pulse plasticity changes not observed in CA1. Furthermore, we demonstrate that transregional metaplasticity, as driven by prior activity in the stratum oriens (SO) in a way that inhibits subsequent LTP in wild-type mice, is occluded in PS19 mice. These data suggest that the tauopathic hippocampus exists in a "metaplastic" state, which inhibits future LTP. Immunofluorescence studies revealed that while astrogliosis and microglial activation were pan-hippocampal, specific neuroinflammatory markers exhibited striking laminar specificity. Mean fluorescence intensity for the neuroinflammatory astrocyte marker C3 was significantly upregulated only in the SO, and the lysosomal marker CD68 showed heightened occupancy specifically in the SO and stratum lacunosum-moleculare. Our findings indicate that tau pathology does not affect the hippocampus uniformly. Instead, it induces region-specific shifts in synaptic efficacy and a breakdown of metaplastic control that coincides with anatomically localized neuroinflammatory signaling.

neuroscience↗

bioRxiv2026

Absence of homeostatic downscaling in dentate gyrus granule cells

Granule cells of the hippocampal dentate gyrus fire at exceptionally low rates in order to maintain sparse neural codes. Despite the need for granule cells to remain in such relative quiescence, the mechanisms that regulate their firing rates have not received much attention. We investigated the potential of family of mechanisms, homeostatic downscaling, that could theoretically maintain granule cell firing at preferential levels following chronically elevated activity. Surprisingly, we found no evidence of reduced synaptic input or intrinsic excitability in granule cells even after prolonged exposure to GABAA receptor blockade. In fact, we found that mini excitatory postsynaptic current frequency was elevated in granule cells after prolonged exposure to GABAA antagonists. This effect was consistent across blockers or when cell firing was driven by elevated extracellular K+, and did not rely on NMDA receptors, L-type voltage gated Ca2+ channels or thrombospondin-driven synaptogenesis. However, the magnitude of long-term potentiation was reduced at synapses onto granule cells after prolonged exposure to a GABAA antagonist in vivo. We conclude that granule cells are the first known cell type that do not display homeostatic downscaling. Instead, these cells rely on other mechanisms, including metaplasticity, to maintain their activity within optimal bounds.

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bioRxiv2025

Perisynaptic astroglial response to in vivo long-term potentiation and concurrent long-term depression in the hippocampal dentate gyrus.

Perisynaptic astroglia provide critical molecular and structural support to regulate synaptic transmission and plasticity in the nanodomain of the axon-spine interface. Three-dimensional reconstruction from serial section electron microscopy (3DEM) was used to investigate relationships between perisynaptic astroglia and dendritic spine synapses undergoing plasticity in the hippocampus of awake adult male rats. Delta-burst stimulation (DBS) of the medial perforant pathway induced long-term potentiation (LTP) in the middle molecular layer and concurrent long-term depression (cLTD) in the outer molecular layer of the dentate gyrus. The contralateral hippocampus received baseline stimulation as a within-animal control. Brains were obtained 30 minutes or 2 hours after DBS onset. An automated 3DEM pipeline was developed to enable unbiased quantification of astroglial coverage at the perimeter of the axon-spine interface. Under all conditions, >85% of synapses had perisynaptic astroglia processes within 120 nm of some portion of the perimeter. LTP broadened the distribution of spine sizes while reducing the presence and proximity of perisynaptic astroglia near the axon-spine interface of large spines. In contrast, cLTD transiently reduced the length of the axon-spine interface perimeter without substantially altering astroglial apposition. The postsynaptic density was discovered to be displaced from the center of the axon-spine interface, with this offset increasing during LTP and decreasing during cLTD. Astroglial access to the postsynaptic density was diminished during LTP and enhanced during cLTD, in parallel with changes in spine size. Thus, access of perisynaptic astroglia to synapses is dynamically modulated during LTP and cLTD alongside synaptic remodeling. Significance StatementPerisynaptic astroglia provide critical molecular and structural regulation of synaptic plasticity underlying learning and memory. The hippocampal dentate gyrus, a brain region crucial for learning and memory, was found to have perisynaptic astroglia at the axon-spine interface of >85% of excitatory synapses measured. Long-term potentiation triggered the retraction of perisynaptic astroglia processes selectively from large synapses. This retraction decreased access of perisynaptic astroglia to the postsynaptic density, which was discovered to be located off-center in the axon-spine interface. Concurrent long-term depression temporarily (< 2 h) decreased spine perimeter and thus increased access of synapses to perisynaptic astroglia. These findings provide new insights into how the structural dynamics of spines and synapses shape access to perisynaptic astroglia.

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bioRxiv2025

Differential Astrocyte-supplied NMDAR Co-Agonist for CA1 versus Dentate Gyrus Long-term Potentiation

In the hippocampus, there is a region and synapse-specific N-methyl-D-aspartate receptor (NMDAR) co-agonist preference for induction of long-term potentiation (LTP). Schaffer collateral (SC)-CA1 synapses, enriched in GluN2A-containing NMDARs, favor D-serine, while medial perforant path (MPP) to dentate gyrus (DG) synapses that are rich in GluN2B-containing NMDARs prefer glycine for LTP induction. This study investigated the role of astrocytes in providing these co-agonists. We confirmed in rat hippocampal slices that exogenous D-serine (10 {micro}M) is sufficient to restore LTP at SC-CA1 synapses blocked under astrocyte calcium (Ca2+) -clamp conditions, consistent with previous findings. However, exogenous glycine (10 M) also rescued the LTP. In contrast, at MPP-DG synapses, 100 {micro}M exogenous glycine, but not 10 {micro}M nor 100 {micro}M D-serine, restored the LTP blocked by astrocyte Ca2+-clamping. Our findings support the view that, as for serine in CA1, astrocytes are the cellular source of the glycine required for LTP induction at MPP-DG synapses.

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bioRxiv2024

An estimate of the longitudinal pace of aging from a single brain scan predicts dementia conversion, morbidity, and mortality

To understand how aging affects functional decline and increases disease risk, it is necessary to develop accurate and reliable measures of how fast a person is aging. Epigenetic clocks measure aging but require DNA methylation data, which many studies lack. Using data from the Dunedin Study, we introduce an accurate and reliable measure for the rate of longitudinal aging derived from cross-sectional brain MRI: the Dunedin Pace of Aging Calculated from NeuroImaging or DunedinPACNI. Exporting this measure to the Alzheimers Disease Neuroimaging Initiative and UK Biobank datasets revealed that faster DunedinPACNI predicted participants cognitive impairment, accelerated brain atrophy, and conversion to diagnosed dementia. Underscoring close links between longitudinal aging of the body and brain, faster DunedinPACNI also predicted physical frailty, poor health, future chronic diseases, and mortality in older adults. Furthermore, DunedinPACNI followed an established socioeconomic health gradient with people of lower socioeconomic status showing faster DunedinPACNI. Associations between DunedinPACNI and cognitive impairment were replicated in BrainLat, a sample of Latin American patients with dementia. When compared to brain age gap, an existing MRI aging biomarker, DunedinPACNI was similarly or more strongly related to clinical outcomes. DunedinPACNI is a "next generation" MRI measure that will be made publicly available to the research community to help accelerate aging research and evaluate the effectiveness of dementia prevention and anti-aging strategies.

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bioRxiv2023

Functional Topography of the Neocortex Predicts Covariation in Complex Cognitive and Basic Motor Abilities

Although higher-order cognitive and lower-order sensorimotor abilities are generally regarded as distinct and studied separately, there is evidence that they not only covary but also that this covariation increases across the lifespan. This pattern has been leveraged in clinical settings where a simple assessment of sensory or motor ability (e.g., hearing, gait speed) can forecast age-related cognitive decline and risk for dementia. However, the brain mechanisms underlying cognitive, sensory, and motor covariation are largely unknown. Here, we examined whether such covariation in midlife reflects variability in common versus distinct neocortical networks using individualized maps of functional topography derived from BOLD fMRI data collected in 769 45-year old members of a population-representative cohort. Analyses revealed that variability in basic motor but not hearing ability reflected individual differences in the functional topography of neocortical networks typically supporting cognitive ability. These patterns suggest that covariation in motor and cognitive abilities in midlife reflects convergence of function in higher-order neocortical networks and that gait speed may not be simply a measure of physical function but rather an integrative index of nervous system health.

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bioRxiv2022

Associations between thinner retinal neuronal layers and suboptimal brain structural integrity: Are the eyes a window to the brain?

We investigated the extent to which measures of retinal neuronal thickness capture variability in the structural integrity of the brain in a large population-based cohort followed from birth to midlife. Using data from the Dunedin Multidisciplinary Health and Development Study (n=1037; analytic n=828, aged 45 years), we specifically tested for associations between optical coherence tomography-measured retinal neuronal layers and MRI-measured structural brain integrity. We found that Study members who had thinner retinal neuronal layers had thinner average cortex, smaller total cortical surface area, smaller subcortical grey matter volumes, larger volume of white matter hyperintensities as well as older looking brains. This suggests that retinal neuronal thickness reflects differences in midlife structural brain integrity consistent with accelerated cognitive decline and increased risk for later dementia, further supporting the proposition that the retina may be a biomarker of brain aging as early as midlife.

neuroscience↗

bioRxiv2022

Regional and LTP-Dependent Variation of Synaptic Information Storage Capacity in Rat Hippocampus

Connectomics is generating an ever-increasing deluge of data, which challenges us to develop new methods for analyzing and extracting insights from these data. We introduce here a powerful method for analyzing three-dimensional reconstruction from serial section electron microscopy (3DEM) to measure synaptic information storage capacity (SISC) and apply it to data following in vivo long-term potentiation (LTP). Connectomic researchers have focused on the pattern of connectivity between neurons. The strengths of synapses have also been studied by quantifying the sizes of synapses. Importantly, synapses from the same axon onto the same dendrite have a common history of coactivation, making them a candidate for measuring the precision of synaptic plasticity based on the similarity of their dimensions. Quantifying precision is fundamental to understanding information storage and retrieval in neural circuits. We quantify this precision with Shannon information theory, which is a more reliable estimate than prior analyses based on signal detection theory because there is no overlap between states, and outliers do not artificially bias the outcome. Spine head volumes are well correlated with other measures of synaptic weight, thus SISC can be determined by identifying the non-overlapping clusters of dendritic spine head volumes to determine the number of distinguishable synaptic weights. SISC analysis of spine head volumes in the stratum radiatum of hippocampal area CA1 revealed 24 distinguishable states (4.1 bits). In contrast, spine head volumes in the middle molecular layer of control dentate gyrus occupied only 5 distinguishable states (2 bits). Thus, synapses in different hippocampal regions had significantly different SISCs. Moreover, these were not fixed properties but increased by 30 min following induction of LTP in the dentate gyrus to occupy 10 distinguishable states (3 bits), and this increase lasted for at least 2 hours. We also observed a broader and nearly uniform distribution of spine head volumes across the increased number of states, suggesting the distribution evolved towards the theoretical upper bound of SISC following LTP. For dentate granule cells these findings show that the spine size range was broadened by the interplay among synaptic plasticity mechanisms. SISC provides a new analytical measure to probe these mechanisms in normal and diseased brains.

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