Biology subjects

Taylor, L. W.

Publications and source records attributed to Taylor, L. W..

6 recordsLinked to original sources

bioRxiv2025

FMRP regulates adult human cortical excitability via cyclic-AMP signalling

Fragile X Syndrome (FXS) is a common inherited neurodevelopmental condition, resulting from loss of Fragile X Messenger Ribonuclear Protein (FMRP). Rodent models of FXS display cellular hyperexcitability, but it is not known to what extent this is the case in intact human neurons. Depleting FMRP in human brain slice cultures reveals cyclic-AMP-dependent cellular hyperexcitability which is corrected by phosphodiesterase 4D inhibition and may be independent of neurodevelopment.

neuroscience↗

bioRxiv2025

Absence of short-term axon initial segment plasticity in human, mouse, and rat cortical circuits

Maintaining neuronal output with respect to input in the physiological range relies on the ability of neurons to update their responsiveness to inputs dependent on changing activity levels. Termed homeostatic plasticity, the mechanisms that neurons employ to control their responsiveness are varied, and proposed to include structural changes to a key neuronal structure - the axon initial segment (AIS). As the site of action potential initiation, the AIS has been postulated to rapidly change its length in response to increased or decreased cellular and circuit activity. To date, AIS structural plasticity has only been tested in tissue cultures and rodent models. In our current study, we assess the ability of neurons to alter their AIS length over a variety of timescales in ex vivo rodent and human brain slices, human neurons derived from induced pluripotent stem cells, and in mice dark-reared during early life; using a combination of electrophysiology and immunohistochemistry. We find no evidence for changes to AIS length following depolarisation for up to 3 hours, despite positive controls confirming modulated activity. However, we do find that neuronal physiological properties are altered by changes in activity - but these are largely independent of action potential initiation associated with the AIS. In summary, we find no evidence supporting a role for AIS structural plasticity in mouse, rat, or human cortical neurons.

neuroscience↗

bioRxiv2024

Phylogenetic divergence of GABAB receptor signalling in neocortical networks over adult life.

Cortical circuit activity is controlled by GABA-mediated inhibition in a spatiotemporally restricted manner. Much is known about fast GABA currents, GABAB receptor (GABABR) signalling exerts powerful slow inhibition that controls synaptic, dendritic and neuronal activity. However, little is known about how GABABRs contribute to circuit-level inhibition over the lifespan of rodents and humans. In this study, we quantitatively determine the functional contribution of GABABR signalling to pre- and postsynaptic domains in rat and human cortical principal cells (PC). We find that postsynaptic GABABR differentially control pyramidal cell activity within the cortical column as a function of age and species, and that these receptors contribute to co-ordination of local information processing in a layer- and species-dependent manner. These data directly increase our knowledge of translationally relevant local circuit dynamics, with direct impact on understanding the role of GABABRs in the treatment of seizure disorders. HighlightsO_LIGABAB receptor signalling displays age and species differences in cortex C_LIO_LIGABAB receptor presynaptic inhibition is stronger in humans than rodents C_LIO_LIIn vitro oscillations in human cortex are strongly regulated by GABABRs C_LIO_LILevetiracetam enhances endogenous GABABR signalling in human cortex C_LI

neuroscience↗

bioRxiv2024

Skeletal muscle myosin heavy chain protein fragmentation as a potential marker of protein degradation in response to resistance training and disuse atrophy

We sought to examine how resistance exercise (RE), cycling exercise, and disuse atrophy affect myosin heavy chain (MyHC) protein fragmentation in humans. In the first study (1boutRE), younger adult men (n=8; 5{+/-}2 years of RE experience) performed a lower body RE bout with vastus lateralis (VL) biopsies obtained immediately before, 3-, and 6-hours post-exercise. In the second study (10weekRT), VL biopsies were obtained in untrained younger adults (n=36, 18 men and 18 women) before and 24 hours (24h) after their first/naive RE bout. These participants also engaged in 10 weeks (24 sessions) of resistance training and donated VL biopsies before and 24h after their last RE bout. VL biopsies were also examined from a third acute cycling study (n=7) and a fourth study involving two weeks of leg immobilization (n=20, 15 men and 5 women) to determine how MyHC fragmentation was affected. In the 1boutRE study, the fragmentation of all MyHC isoforms (MyHCTotal) increased 3 hours post-RE ([~] +200%, p=0.018) and returned to pre-exercise levels by 6 hours post-RE. Immunoprecipitation of MyHCTotal revealed ubiquitination levels remained unaffected at the 3- and 6-hour post-RE time points. Interestingly, a greater increase in magnitude for MyHC type IIa versus I isoform fragmentation occurred 3-hours post-RE (8.6{+/-}6.3-fold versus 2.1{+/-}0.7-fold, p=0.018). In all 10weekRT participants, the first/naive and last RE bouts increased MyHCTotal fragmentation 24h post-RE (+65% and +36%, respectively; p<0.001); however, the last RE bout response was attenuated compared to the first bout (p=0.045). The first/naive bout response was significantly elevated in females only (p<0.001), albeit females also demonstrated a last bout attenuation response (p=0.002). Although an acute cycling bout did not alter MyHCTotal fragmentation, [~]8% VL atrophy with two weeks of leg immobilization led to robust MyHCTotal fragmentation (+108%, p<0.001), and no sex-based differences were observed. In summary, RE and disuse atrophy increase MyHC protein fragmentation. A dampened response with 10 weeks of resistance training, and more refined responses in well-trained men, suggest this is an adaptive process. Given the null polyubiquitination IP findings, more research is needed to determine how MyHC fragments are processed. Moreover, further research is needed to determine how aging and disease-associated muscle atrophy affect these outcomes, and whether MyHC fragmentation is a viable surrogate for muscle protein turnover rates.

molecular biology↗

bioRxiv2024

Opposing roles of physiological and pathological amyloid-β on synapses in live human brain slice cultures

In Alzheimers disease, it is theorised that amyloid beta (A{beta}) and tau pathology contribute to synapse loss. However, there is limited information on how endogenous levels of tau and A{beta} protein relate to patient characteristics, or how manipulating physiological levels of A{beta} impacts synapses, in living adult, human brain. Here, we employed live human brain slice cultures as a translational tool to assess endogenous tau and A{beta} release, pathology, and response to experimental manipulation. We found that the levels of A{beta}1-40 and tau detected in the culture medium depend on donor age, and brain region, respectively. Pharmacologically raising physiological A{beta} concentration enhanced levels of synaptic transcripts. Treatment of slices with A{beta}-containing Alzheimers disease brain extract resulted in postsynaptic A{beta} uptake and loss of presynaptic puncta. These data indicate that physiological and pathological A{beta} can have opposing effects on synapses in living human brain tissue.

neuroscience↗

bioRxiv2023

Tau phosphorylated at serine 356 is associated with Alzheimer's disease pathology and can be lowered in mouse and human brain tissue using the NUAK inhibitor WZ4003

Tau hyperphosphorylation and aggregation is a common feature of many dementia-causing neurodegenerative diseases. Tau can be phosphorylated at up to 85 different sites, and there is increasing interest in whether tau phosphorylation at specific epitopes, by specific kinases, plays an important role in disease progression. The AMP-activated protein kinase (AMPK) related enzyme NUAK1 been identified as a potential mediator of tau pathology, whereby NUAK1-mediated phosphorylation of tau at Ser356 prevents the degradation of tau by the proteasome, further exacerbating tau hyperphosphorylation and accumulation. This study provides a detailed characterisation of the association of p-tau Ser356 with progression of Alzheimers disease pathology, identifying a Braak stage-dependent increase in p-tau Ser356 protein levels and an almost ubiquitous presence in neurofibrillary tangles. We also demonstrate, using sub-diffraction-limit resolution array tomography imaging, that p-tau Ser356 co-localises with synapses in AD post-mortem brain tissue, increasing evidence that this form of tau may play important roles in AD progression. To assess the potential impacts of pharmacological NUAK inhibition in an ex vivo system that retains multiple cell types and brain-relevant neuronal architecture, we treated postnatal mouse organotypic brain slice cultures from wildtype or APP/PS1 littermates with the commercially available NUAK1/2 inhibitor WZ4003. Whilst there were no genotype specific effects, we found that WZ4003 results in a culture-phase dependent loss of total tau and p-tau Ser356, which corresponds with a reduction in neuronal and synaptic proteins. By contrast, application of WZ4003 to live human brain slice cultures results in a specific lowering of p-tau Ser356, alongside increased neuronal tubulin protein. This work identifies differential responses of postnatal mouse organotypic brain slice cultures and adult human brain slice cultures to NUAK1 inhibition that will be important to consider in future work developing tau-targeting therapeutics for human disease.

neuroscience↗