Biology subjects

Bonthron, C.

Publications and source records attributed to Bonthron, C..

3 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

Direct Evidence for Dendritic Spine Compensation and Regeneration in Alzheimer Disease Models

Dendritic spine loss in Alzheimers disease (AD) strongly correlates with cognitive decline, whereas spine preservation is associated to cognitive resilience. Yet, whether and how neurons compensate for spine loss in AD remains largely unknown. Using a chromophore-assisted light inactivation approach (CALI), we developed a tool to selectively eliminate dendritic spines to model this key feature of AD. Using in vivo and in vitro two-photon imaging, we discovered that the artificial elimination of spines triggers a two-stage compensatory response: rapid enlargement of remaining spines followed by delayed spine regeneration. Remarkably, similar structural plasticity was observed across multiple {beta}-amyloid-driven models of synapse loss, including the APP/PS1 mouse and following intracortical delivery of oligomeric {beta}-amyloid. Mechanistically, compensatory spine enlargement required NMDA receptor activation and de novo protein synthesis. These findings suggest that neurons retain an intrinsic capacity to reverse early synaptic loss in AD, potentially contributing to cognitive resilience.

neuroscience↗

bioRxiv2021

Selective Vulnerability of Tripartite Synapses in Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder. Separate lines of evidence suggest that synapses and astrocytes play a role in the pathological mechanisms underlying ALS. Given that astrocytes make specialised contacts with some synapses, called tripartite synapses, we hypothesise that tripartite synapses could act as the fulcrum of disease in ALS. To test this hypothesis, we have performed an extensive microscopy-based investigation of synapses and tripartite synapses in the spinal cord of ALS model mice and post-mortem human tissue from ALS cases. We reveal widescale synaptic changes at the early symptomatic stages of the SOD1G93a mouse model. Super-resolution microscopy reveals that large complex postsynaptic structures are lost in ALS mice. Most surprisingly, tripartite synapses are selectively lost while non-tripartite synapses remain in equal number to healthy controls. Finally, we also observe a similar selective loss of tripartite synapses in human post-mortem ALS spinal cords. From these data we conclude that tripartite synaptopathy is a key hallmark of ALS.

neuroscience↗