Biology subjects

Murray, T. K.

Publications and source records attributed to Murray, T. K..

3 recordsLinked to original sources

bioRxiv2023

Synaptic alterations associated with disrupted sensory encoding in a mouse model of tauopathy

Synapse loss is currently the best biological correlate of cognitive decline in Alzheimers disease and other tauopathies. Synapses seem to be highly vulnerable to tau-mediated disruption in neurodegenerative tauopathies. However, it is unclear how and when this leads to alterations in function in relation to the progression of tauopathy and neurodegeneration. We used the well-characterised rTg4510 mouse model of tauopathy, at 5-6 months and 7-8 months of age, to study the functional impact of cortical synapse loss. The earlier age was used as a model of prodromal tauopathy, with the later age corresponding to more advanced tau pathology and presumed progression of neurodegeneration. Analysis of synaptic protein expression in the somatosensory cortex showed significant reductions in synaptic proteins and NMDA and AMPA receptor subunit expression in rTg4510 mice. Surprisingly, in vitro whole-cell patch clamp electrophysiology from putative pyramidal neurons in layer 2/3 of the somatosensory cortex suggested no functional alterations in layer 4 to layer 2/3 synaptic transmission at 5-6 months. From these same neurons, however, there were alterations in dendritic structure, with increased branching seen proximal to the soma in rTg4510 neurons. Therefore, in vivo whole-cell patch clamp recordings were utilised to investigate synaptic function and integration in putative pyramidal neurons in layer 2/3 of the somatosensory cortex. These recordings revealed a significant increase in the peak response to synaptically-driven sensory stimulation-evoked activity and a loss of temporal fidelity of the evoked signal to the input stimulus in rTg4510 neurons. Together, these data suggest that loss of synapses, changes in receptor expression, and dendritic restructuring may lead to alterations in synaptic integration at a network level. Understanding of these compensatory processes could identify targets to help delay symptomatic onset within dementia. Abbreviated summaryMeftah et al. report alterations to synaptic and dendrite properties in the rTg4510 mouse model of tauopathy associated with disrupted synaptic integration in vivo. Therefore, disrupted synaptic and network integration may be early markers of synapse loss in neurodegenerative tauopathies.

neuroscience↗

bioRxiv2020

Differential aberrant structural synaptic plasticity in axons and dendrites ahead of their degeneration in tauopathy

Neurodegeneration driven by aberrant tau is a key feature of many dementias. Pathological stages of tauopathy are characterised by reduced synapse density and altered synapse function. Furthermore, changes in synaptic plasticity have been documented in the early stages of tauopathy suggesting that they may be a driver of later pathology. However, it remains unclear if synapse plasticity is specifically linked to the degeneration of neurons. This is partly because, in progressive dementias, pathology can vary widely from cell-to-cell along the prolonged disease time-course. To overcome this variability, we have taken a longitudinal experimental approach to track individual neurons through the progression of neurodegenerative tauopathy. Using repeated in vivo 2-photon imaging in rTg4510 transgenic mice, we have measured structural plasticity of presynaptic terminaux boutons and postsynaptic spines on individual axons and dendrites over long periods of time. By following individual neurons, we have measured synapse density across the neuronal population and tracked changes in synapse turnover in each neuron. We found that tauopathy drives a reduction in density of both presynaptic and postsynaptic structures and that this is partially driven by degeneration of individual axons and dendrites that are spread widely across the disease time-course. Both synaptic loss and neuronal degeneration was ameliorated by reduction in expression of the aberrant P301L transgene, but only if that reduction was initiated early in disease progression. Notably, neurite degeneration was preceded by alterations in synapse turnover that contrasted in axons and dendrites. In dendrites destined to die, there was a dramatic loss of spines in the week immediately before degeneration. In contrast, axonal degeneration was preceded by a progressive attenuation of presynaptic turnover that started many weeks before axon disappearance. Therefore, changes in synapse plasticity are harbingers of degeneration of individual neurites that occur at differing stages of tau-driven neurodegenerative disease, suggesting a cell or neurite autonomous process. Furthermore, the links between synapse plasticity and degeneration are distinct in axonal and dendritic compartments. Key findingsO_LITauopathy driven by tau P301L in rTg4510 mice causes a progressive decrease in density of presynaptic terminaux boutons and postsynaptic dendritic spines in cortical excitatory neurons. C_LIO_LILongitudinal imaging of individual axons and dendrites shows that there is a huge diversity of effects at varying times in different cells. C_LIO_LIDecreases in overall synapse density are driven partly, but not exclusively, by degeneration of dendrites and axons that are distributed widely across the time-course of disease. C_LIO_LISuppression of pathological P301L tau expression can ameliorate accumulation of tau pathology, synapse loss and neurodegeneration, but only if administered early in disease progression. C_LIO_LINeurite degeneration is preceded by aberrant structural synaptic plasticity in a cell-specific way that is markedly different in dendrites and axons. C_LIO_LIDegeneration of dendrites is immediately preceded by dramatic loss of dendritic spines. C_LIO_LIAxonal loss is characterised by a progressive attenuation of presynaptic bouton plasticity that starts months before degeneration. C_LI

neuroscience↗

bioRxiv2019

Transcriptional signatures of progressive neuropathology in transgenic tau and amyloid mouse models.

The onset and progression of Alzheimers disease (AD) is characterized by increasing intracellular aggregation of hyperphosphorylated tau protein and accumulation of {beta}-amyloid (A{beta}) in the neocortex. Despite recent success in identifying genetic risk factors for AD the transcriptional mechanisms involved in disease progression are not fully understood. We used transgenic mice harbouring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the development of both tau and amyloid pathology. Using highly-parallel RNA sequencing we profiled transcriptional variation in the entorhinal cortex at four time points identifying robust genotype-associated differences in entorhinal cortex gene expression in both models. We quantified neuropathological burden across multiple brain regions in the same individual mice, identifying widespread changes in gene expression paralleling the development of tau pathology in rTg4510 mice. Differentially expressed transcripts included genes associated with familial AD from genetic studies of human patients, and genes annotated to both common and rare variants identified in GWAS and exome-sequencing studies of late-onset sporadic AD. Systems-level analyses identified discrete co-expression networks associated with the progressive accumulation of tau, with these enriched for genes and pathways previously implicated in the neuro-immunological and neurodegenerative processes driving AD pathology. Finally, we report considerable overlap between tau-associated networks and AD-associated co-expression modules identified in the human cortex. Our data provide further support for an immune-response component in the accumulation of tau, and reveal novel molecular pathways associated with the progression of AD neuropathology.

genomics↗