Biology subjects

Blizzard, C.

Publications and source records attributed to Blizzard, C..

3 recordsLinked to original sources

bioRxiv2025

Myelin maintenance and addition regulate synaptic plasticity in the adult mouse cortex

Myelination of the developing central nervous system (CNS) increases action potential conduction velocity but can also act as a plasticity brake, limiting neurite reorganisation and synaptic plasticity. As myelination is a life-long process, the myelin laid down in development or adulthood could also affect synapse number or plasticity across the lifespan. We report that conditionally deleting the transcription factor, myelin regulatory factor (Myrf), to disrupt the myelin maintenance program in oligodendrocytes (OLs) from P57 (Plp-CreERT2 :: Myrf fl/fl mice), led to significant myelin loss and impaired action potential conduction and gross motor performance. By sparsely labelling layer V pyramidal neurons in the primary motor cortex, we could visualise the apical and basal dendrites and their excitatory post-synaptic dendritic spines and determined that spine density was normal in P57+60 Plp-CreERT2 :: Myrf fl/fl mice. However, a higher proportion of the dendritic spines were large, stable mushroom spines and generated larger amplitude miniature excitatory post-synaptic currents. These data indicate that the myelin maintenance program is critical for preserving neuron adaptability, homeostasis and glutamate sensitivity. When we instead prevented the addition of new OLs and myelin from P57, action potential conduction velocity and gross motor performance appeared normal. Spine density was also normal in Pdgfr-CreERTM :: Myrf fl/fl mice, however, spine morphology was changed along the basal dendrites of layer V M1 pyramidal neurons. At P117, the basal dendrites were frozen in a state that resembled P57 dendrites, as they retained a higher proportion of thin, plastic spines. These data suggest that adult myelination supports the life-long accumulation of stable spines within the basal but not apical dendritic compartment and have important implications for understanding dendritic plasticity rules in the motor circuit. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/695322v1_ufig1.gif" ALT="Figure 1"> View larger version (77K): org.highwire.dtl.DTLVardef@1a7928org.highwire.dtl.DTLVardef@83e7borg.highwire.dtl.DTLVardef@13e1e14org.highwire.dtl.DTLVardef@128e2df_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAdult myelin maintenance regulates synaptic plasticity and neuron homeostasis C_LIO_LIExisting myelin regulates layer V pyramidal neuron glutamate sensitivity C_LIO_LIOligodendrocytes born in young adulthood undergo age-related loss C_LIO_LINew myelin stabilises synapses in the basal but not apical dendritic compartment C_LI eTOC blurbMyelin regulates axon branching, metabolism and action potential conduction speed. We report that myelin also preserves neuron adaptability, homeostasis and glutamate sensitivity in the adult motor cortex. Furthermore, new myelin allows the accumulation of stable synapse on basal but not apical layer V pyramidal neuron dendrites over time.

neuroscience↗

bioRxiv2025

Synaptic changes contribute to persistent extra-motor behaviour deficits in the rNLS8 TDP-43 mouse model of amyotrophic lateral sclerosis

Extra-motor symptoms are increasingly recognised in amyotrophic lateral sclerosis (ALS), encompassing cognitive, social, and behavioural deficits that can substantially impact quality of life. TAR DNA binding protein 43 (TDP-43) pathology is the central disease marker of almost all cases of ALS and approximately half of all frontotemporal dementia (FTD). However, the mechanisms linking TDP-43 pathology with extra-motor symptoms in TDP-43-associated neurodegenerative diseases remain unresolved. In this study, we used the rNLS8 mouse model, which expresses human TDP-43 with an ablated nuclear localisation sequence (hTDP-43∆NLS) in a doxycycline-regulatable manner causing progressive motor decline reminiscent of ALS, to delineate the molecular changes associated with disease-relevant phenotypes. We found that in addition to previously reported dramatic motor decline, rNLS8 mice also develop extra-motor phenotypes consistent with FTD, including disinhibition-like and anxiety-like behaviours, and social interaction impairments. These changes began in the earliest disease stages and remained readily detectable even when rNLS8 mice became severely motor impaired. Notably, extra-motor deficits persisted in rNLS8 mice that had recovered motor function upon hTDP-43∆NLS transgene suppression, regardless of whether recovery was initiated at timepoints prior to or after overt neurodegeneration begins. Transcriptomic analysis of rNLS8 mouse cortex tissues revealed early alterations in expression of 321 genes, most notably involving neuroinflammatory-related pathway activation, and all but 2 of these genes returned to control levels upon suppression of hTDP-43∆NLS expression. Further, 814 genes showed differential exon usage, indicating changes in alternative splicing, in rNLS8 mouse cortex. Of these, differential exon usage of 10 neuronal genes persisted after hTDP-43∆NLS transgene suppression, including synapse component genes Nrxn1, Unc13a, and Gls. Similarly, proteomics analysis of the cortex of rNLS8 mice revealed depletion of synaptic proteins, particularly those involved in glutamatergic signalling pathways, which also persisted following hTDP-43∆NLS transgene suppression. Similar glutamatergic pathway changes were detected in human ALS and FTD post-mortem cortex tissues. Our findings indicate that extra-motor phenotypes emerge early in disease in rNLS8 mice and remain evident despite progressive motor impairments. Further, extra-motor phenotypes persist even upon motor recovery, correlating with specific synaptic gene expression and splicing changes. Overall, this study suggests the potential utility of an expanded suite of behavioural paradigms in preclinical testing using rNLS8 mice, with enhanced relevance to the diversity of TDP-43 proteinopathies including FTD. Our findings further suggest that targeting glutamatergic synaptic components may be an avenue to correct extra-motor deficits associated with TDP-43 pathology.

neuroscience↗

bioRxiv2024

Biological sex determines skeletal muscle atrophy in response to cortical TDP-43 pathology

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative condition. In ALS, wasting of skeletal muscle causes weakness, paralysis and ultimately, death due to respiratory failure. Diagnosis of ALS is a long process and delays in diagnosis are common, which impedes rapid provision of patient care and treatment. Additional tools or methodologies that improve early detection might help overcome the diagnostic delays and enhance survival and quality of life for people with ALS. In this study, we used a transgenic mouse model to create a detailed catalogue of skeletal muscle wasting with the goal of finding muscles that can be examined to enhance early diagnosis of ALS. MethodsCortical pathology was induced by crossing CaMKIIa-tTA and tetO-hTDP-43{Delta}NLS transgenic mice ({Delta}NLS). Transgenic expression was induced at 30-days postnatal via removal of doxycycline diet. Mice were aged to 15-, 20-, 30- and 45-days post transgene induction. Microdissection was applied to isolate 22 individual hindlimb muscles for measurement of weight. Both males and females were used at all timepoints. ResultsWe found that male and female {Delta}NLS mice exhibited hindlimb skeletal muscle atrophy relative to controls. Multiply innervated muscles, also known as series-fibered muscles, were especially vulnerable to atrophy. The strongest predictor of the atrophic response across all hindlimb muscles was the extent to which any individual muscle was larger in males than females, known also as sexual dimorphism. In males, muscles that are usually larger in males compared to females experienced the most atrophy. Conversely, in females, muscles that are usually of similar size between males and females experienced the most atrophy. Segregating muscles based on whether they were more affected in males or females revealed that hip extensors, knee flexors, knee extensors, ankle dorsiflexors and ankle evertors were more affected in males. Hip adductors, hip rotators, hip flexors and ankle plantarflexors were more affected in females. ConclusionsOur results demonstrate that the difference in the size of skeletal muscles in males compared to females is the most powerful predictor of muscle atrophy in response to dying forward pathology. This indicates that sex is a strong determinant of skeletal muscle vulnerability in ALS. Our results provide new insights into determinants of skeletal muscle atrophy and may help inform selection of muscles for diagnostic testing of ALS patients.

neuroscience↗