Biology subjects

Kramar, E.

Publications and source records attributed to Kramar, E..

4 recordsLinked to original sources

bioRxiv2025

Inhibition of histone lysine demethylase restores learning and memory in aged mice

Chromatin undergoes dramatic changes during the ageing process. In the brain, these chromatin changes are thought to underlie age-associated deficits in the activity-dependent gene transcription necessary for memory consolidation. Here, we show that the levels of a specific histone post-translational modification (PTM), trimethylation of lysine 4 on histone 3 (H3K4me3) is markedly increased in the hippocampus of aged mice and that the activity-induced increase in H3K4me3 that is observed in response to a learning stimulus in young mice, is severely blunted in the aged hippocampus. H3K4me3 typically marks open, accessible chromatin at the transcriptional start sites (TSSs) of actively transcribed genes. We identify altered H3K4me3 peaks at TSSs and show that ca. 90% of the activity-induced H3K4me3 changes at TSSs are either absent or reduced in the aged hippocampus. To understand the biological significance of these age-associated changes, we screened a library of pharmacological compounds for compounds that can alter H3K4me3 levels in hippocampal neurons. We show that treatment of aged mice with one of these, the LSD1 inhibitor ORY-1001, restored normal learning and memory in object location and recognition tasks. Furthermore, we show that ORY-1001 treatment increased long-term potentiation (LTP), a form of synaptic plasticity deficient in the aged hippocampus. These findings suggest that targeting the epigenetic machinery that regulates activity-dependent gene transcription may represent an avenue for treating age-associated cognitive impairment. HighlightsO_LIH3K4me3 levels are elevated in the naive aged mouse hippocampus C_LIO_LIActivity-dependent H3K4me3 induction is impaired in the aged mouse hippocampus C_LIO_LILSD1 inhibition restores learning and memory in aged mice C_LIO_LILSD1 inhibition restores activity-dependent Arc induction and increases LTP in the aged hippocampus C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/695858v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@fccd92org.highwire.dtl.DTLVardef@11c4d93org.highwire.dtl.DTLVardef@128f8b8org.highwire.dtl.DTLVardef@e1341f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

A multi-institutional study to investigate the sparing effect after whole brain electron FLASH in mice: Reproducibility and temporal evolution of functional, electrophysiological, and neurogenic endpoints

PurposeUltra-high dose-rate radiotherapy (FLASH) has been shown to mitigate normal tissue toxicities associated with conventional dose rate radiotherapy (CONV) without compromising tumor killing in preclinical models. A prominent challenge in preclinical radiation research, including FLASH, is validating both the physical dosimetry and the biological effects across multiple institutions. MethodsWe previously demonstrated dosimetric reproducibility of two different electron FLASH devices at separate institutions using standardized phantoms and dosimeters. In this study, we compared the outcome of FLASH and CONV 10 Gy whole brain irradiation on female adult mice at both institutions to evaluate the reproducibility and temporal evolution of multiple endpoints. ResultsFLASH sparing of behavioral performance on novel object recognition (4 months post-irradiation) and electrophysiologic long-term potentiation (LTP, 5-months post-irradiation) was reproduced between institutions. Interestingly, differences between FLASH and CONV on the endpoints of hippocampal neurogenesis (Sox2, doublecortin), neuroinflammation (microglial activation), and electrophysiology (LTP) at late times were not observed at early times. ConclusionsIn summary, we demonstrated reproducible FLASH sparing effects between two beams and two institutions with validated dosimetry. FLASH sparing effects on the endpoints evaluated manifested at late but not early time points.

cancer biology↗

bioRxiv2023

C5aR1 signaling promotes region and age dependent synaptic pruning in models of Alzheimers Disease

INTRODUCTIONSynaptic loss is a hallmark of Alzheimers disease (AD) that correlates with cognitive decline in AD patients. Complement-mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 inhibition on microglial and astroglial synaptic pruning in two mouse models of AD. METHODSA combination of super-resolution and confocal and tridimensional image reconstruction was used to assess the effect of genetic ablation or pharmacological inhibition of C5aR1 on the Arctic48 and Tg2576 models of AD. RESULTSGenetic ablation or pharmacological inhibition of C5aR1 rescues the excessive pre-synaptic pruning and synaptic loss in an age and region dependent fashion in two mouse models of AD, which correlates with improved long-term potentiation (LTP). DISCUSSIONReduction of excessive synaptic pruning is an additional beneficial outcome of the suppression of C5a-C5aR1 signaling, further supporting its potential as an effective targeted therapy to treat AD.

neuroscience↗

bioRxiv2019

A Unique Mouse Model of Early-Life Exercise Enables Lasting Hippocampal Synaptic Plasticity and Memory

Aerobic exercise is a powerful modulator of learning and memory. Molecular mechanisms underlying the cognitive benefits of exercise are well documented in adult rodents. Animal models of exercise targeting specific postnatal periods of hippocampal development and plasticity are lacking. Here we characterize a model of early-life exercise (ELE) in male and female mice designed with the goal of identifying critical periods by which exercise may have a lasting impact on hippocampal memory and synaptic plasticity. Mice freely accessed a running wheel during three postnatal periods: the 4th postnatal week (juvenile ELE, P21-27), 6th postnatal week (adolescent ELE, P35-41), or 4th-6th postnatal weeks (juvenile-adolescent ELE, P21-41). All exercise groups significantly increased their running distances over time. When exposed to a weak learning stimulus, mice that had exercised during the juvenile period were able to form lasting long-term memory for a hippocampus-dependent spatial memory task. Electrophysiological experiments revealed enhanced long-term potentiation in hippocampal CA1 the juvenile-adolescent ELE group only. Furthermore, basal synaptic transmission was significantly increased in all mice that exercised during the juvenile period. Our results suggest early-life exercise can enable hippocampal memory, synaptic plasticity, and basal synaptic physiology when occurring during postnatal periods of hippocampal maturation.

neuroscience↗