KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions

Kmt2a and Kmt2b are H3K4 methyltransferases of the Set1/Trithorax class. We have recently shown the importance of Kmt2b for learning and memory. Here, we report that Kmt2a is also important in memory formation. We compare the decrease in H3K4 methylation and de-regulation of gene expression in hippocampal neurons of mice with knockdown of either Kmt2a or Kmt2b. Kmt2a and Kmt2b control largely distinct genomic regions and different molecular pathways linked to neuronal plasticity. Finally, we show that the decrease in H3K4 methylation resulting from Kmt2a knockdown partially recapitulates the pattern previously reported in CK-p25 mice, a model for neurodegeneration and memory impairment. Our findings point to the distinct functions of even closely related histone-modifying enzymes and provide essential insight for the development of more efficient and specific epigenetic therapies against brain diseases.Beca Ramón y CajalGAIN- Agencia Gallega de Innovació

Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance

The acquisition of language and speech is uniquely human, but how genetic changes might have adapted the nervous system to this capacity is not well understood. Two human-specific amino acid substitutions in the transcription factor forkhead box P2 (FOXP2) are outstanding mechanistic candidates, as they could have been positively selected during human evolution and as FOXP2 is the sole gene to date firmly linked to speech and language development. When these two substitutions are introduced into the endogenous Foxp2 gene of mice (Foxp2[superscript hum]), cortico-basal ganglia circuits are specifically affected. Here we demonstrate marked effects of this humanization of Foxp2 on learning and striatal neuroplasticity. Foxp2[superscript hum/hum] mice learn stimulus–response associations faster than their WT littermates in situations in which declarative (i.e., place-based) and procedural (i.e., response-based) forms of learning could compete during transitions toward proceduralization of action sequences. Striatal districts known to be differently related to these two modes of learning are affected differently in the Foxp2[superscript hum/hum] mice, as judged by measures of dopamine levels, gene expression patterns, and synaptic plasticity, including an NMDA receptor-dependent form of long-term depression. These findings raise the possibility that the humanized Foxp2 phenotype reflects a different tuning of corticostriatal systems involved in declarative and procedural learning, a capacity potentially contributing to adapting the human brain for speech and language acquisition.Nancy Lurie Marks Family FoundationSimons Foundation (Autism Research Initiative Grant 137593)National Institutes of Health (U.S.) (Grant R01 MH060379)Wellcome Trust (London, England) (Grant 075491/Z/04)Wellcome Trust (London, England) (Grant 080971)Fondation pour la recherche medicaleMax Planck Society for the Advancement of Scienc

Formin 2 links neuropsychiatric phenotypes at young age to an increased risk for dementia

Age-associated memory decline is due to variable combinations of genetic and environmental risk factors. How these risk factors interact to drive disease onset is currently unknown. Here we begin to elucidate the mechanisms by which post-traumatic stress disorder (PTSD) at a young age contributes to an increased risk to develop dementia at old age. We show that the actin nucleator Formin 2 (Fmn2) is deregulated in PTSD and in Alzheimer's disease (AD) patients. Young mice lacking the Fmn2 gene exhibit PTSD-like phenotypes and corresponding impairments of synaptic plasticity, while the consolidation of new memories is unaffected. However, Fmn2 mutant mice develop accelerated age-associated memory decline that is further increased in the presence of additional risk factors and is mechanistically linked to a loss of transcriptional homeostasis. In conclusion, our data present a new approach to explore the connection between AD risk factors across life span and provide mechanistic insight to the processes by which neuropsychiatric diseases at a young age affect the risk for developing dementia

Effect of Coenzyme Q10 on ischemia and neuronal damage in an experimental traumatic brain-injury model in rats

<p>Abstract</p> <p>Background</p> <p>Head trauma is one of the most important clinical issues that not only can be fatal and disabling, requiring long-term treatment and care, but also can cause heavy financial burden. Formation or distribution of free oxygen radicals should be decreased to enable fixing of poor neurological outcomes and to prevent neuronal damage secondary to ischemia after trauma. Coenzyme Q₁₀(CoQ₁₀), a component of the mitochondrial electron transport chain, is a strong antioxidant that plays a role in membrane stabilization. In this study, the role of CoQ₁₀in the treatment of head trauma is researched by analyzing the histopathological and biochemical effects of CoQ₁₀administered after experimental traumatic brain injury in rats. A traumatic brain-injury model was created in all rats. Trauma was inflicted on rats by the free fall of an object of 450 g weight from a height of 70 cm on the frontoparietal midline onto a metal disc fixed between the coronal and the lambdoid sutures after a midline incision was carried out.</p> <p>Results</p> <p>In the biochemical tests, tissue malondialdehyde (MDA) levels were significantly higher in the traumatic brain-injury group compared to the sham group (<it>p </it>< 0.05). Administration of CoQ₁₀after trauma was shown to be protective because it significantly lowered the increased MDA levels (<it>p </it>< 0.05). Comparing the superoxide dismutase (SOD) levels of the four groups, trauma + CoQ₁₀group had SOD levels ranging between those of sham group and traumatic brain-injury group, and no statistically significant increase was detected. Histopathological results showed a statistically significant difference between the CoQ₁₀and the other trauma-subjected groups with reference to vascular congestion, neuronal loss, nuclear pyknosis, nuclear hyperchromasia, cytoplasmic eosinophilia, and axonal edema (<it>p </it>< 0.05).</p> <p>Conclusion</p> <p>Neuronal degenerative findings and the secondary brain damage and ischemia caused by oxidative stress are decreased by CoQ₁₀use in rats with traumatic brain injury.</p

KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions

Kmt2a and Kmt2b are H3K4 methyltransferases of the Set1/Trithorax class. We have recently shown the importance of Kmt2b for learning and memory. Here, we report that Kmt2a is also important in memory formation. We compare the decrease in H3K4 methylation and de-regulation of gene expression in hippocampal neurons of mice with knockdown of either Kmt2a or Kmt2b. Kmt2a and Kmt2b control largely distinct genomic regions and different molecular pathways linked to neuronal plasticity. Finally, we show that the decrease in H3K4 methylation resulting from Kmt2a knockdown partially recapitulates the pattern previously reported in CK-p25 mice, a model for neurodegeneration and memory impairment. Our findings point to the distinct functions of even closely related histone-modifying enzymes and provide essential insight for the development of more efficient and specific epigenetic therapies against brain diseases

Atmospheric stilling leads to prolonged thermal stratification in a large shallow polymictic lake

To quantify the effects of recent and potential future decreases in surface wind speeds on lake thermal stratification, we apply the one-dimensional process-based model MyLake to a large, shallow, polymictic lake, Võrtsjärv. The model is validated for a 3-year period and run separately for 28 years using long-term daily atmospheric forcing data from a nearby meteorological station. Model simulations show exceptionally good agreement with observed surface and bottom water temperatures during the 3-year period. Similarly, simulated surface water temperatures for 28 years show remarkably good agreement with long-term in situ water temperatures. Sensitivity analysis demonstrates that decreasing wind speeds has resulted in substantial changes in stratification dynamics since 1982, while increasing air temperatures during the same period had a negligible effect. Atmospheric stilling is a phenomenon observed globally, and in addition to recent increases in surface air temperature, needs to be considered when evaluating the influence of climate change on lake ecosystems

Effects of Nutrient Management Scenarios on Marine Eutrophication Indicators: A Pan-European, Multi-Model Assessment in Support of the Marine Strategy Framework Directive

A novel pan-European marine model ensemble was established, covering nearly all seas under the regulation of the Marine Strategy Framework Directive (MSFD), with the aim of providing a consistent assessment of the potential impacts of riverine nutrient reduction scenarios on marine eutrophication indicators. For each sea region, up to five coupled biogeochemical models from institutes all over Europe were brought together for the first time. All model systems followed a harmonised scenario approach and ran two simulations, which varied only in the riverine nutrient inputs. The load reductions were evaluated with the catchment model GREEN and represented the impacts due to improved management of agriculture and wastewater treatment in all European river systems. The model ensemble, comprising 15 members, was used to assess changes to the core eutrophication indicators as defined within MSFD Descriptor 5. In nearly all marine regions, riverine load reductions led to reduced nutrient concentrations in the marine environment. However, regionally the nutrient input reductions led to an increase in the non-limiting nutrient in the water, especially in the case of phosphate concentrations in the Black Sea. Further core eutrophication indicators, such as chlorophyll-a, bottom oxygen and the Trophic Index TRIX, improved nearly everywhere, but the changes were less pronounced than for the inorganic nutrients. The model ensemble displayed strong consistency and robustness, as most if not all models indicated improvements in the same areas. There were substantial differences between the individual seas in the speed of response to the reduced nutrient loads. In the North Sea ensemble, a stable plateau was reached after only three years, while the simulation period of eight years was too short to obtain steady model results in the Baltic Sea. The ensemble exercise confirmed the importance of improved management of agriculture and wastewater treatments in the river catchments to reduce marine eutrophication. Several shortcomings were identified, the outcome of different approaches to compute the mean change was estimated and potential improvements are discussed to enhance policy support. Applying a model ensemble enabled us to obtain highly robust and consistent model results, substantially decreasing uncertainties in the scenario outcom