Dynamic epigenetic mechanisms including histone and DNA modifications regulate animal behavior and memory. While numerous enzymes regulating these mechanisms have been linked to memory formation, the regulation of active DNA demethylation (i.e. – cytosine-5 demethylation) has only recently been investigated. New discoveries aim towards the Gadd45 family, particularly Gadd45b, in activity-dependent demethylation in the adult CNS. This study found memory-associated expression of gadd45b in the hippocampus and characterized the behavioral phenotype of gadd45b−/− mice. Results indicate normal baseline behaviors and initial learning but enhanced persisting memory in mutants in tasks of motor performance, aversive conditioning and spatial navigation. Furthermore, we showed facilitation of hippocampal long-term potentiation in mutants. These results implicate Gadd45b as a learning-induced gene and a regulator of memory formation and are consistent with its potential role in active DNA demethylation in memory.

Background and Objective Periodontitis is a serious disease that affects the majority of adult population around the world. While great efforts have been devoted toward understanding the pathogenesis of periodontitis, there remains a pressing need for developing potent therapeutic strategies for targeting this dreadful disease. In this study, we utilized adeno-associated virus (AAV) expressing Cathepsin K (Ctsk) shRNA (AAV-sh-Ctsk) to silence Ctsk in vivo and subsequently evaluated its impact in periodontitis as a potential therapeutic strategy for this disease. Material and Methods We used a known mouse model of periodontitis, in which wild-type BALB/cJ mice were infected with Porphyromonas gingivalis W50 (P. gingivalis) in the maxillary and mandibular periodontium to induce the disease. AAV-sh-Ctsk was then administrated locally into the periodontal tissues in vivo, followed by analyses to assess the progression of the disease. Results AAV-mediated Ctsk silencing drastically protected mice (>80%) from P. gingivalis-induced bone resorption by osteoclasts. Also, AAV-sh-Ctsk administration drastically reduced inflammation by impacting the expression of many inflammatory cytokines as well as T cell and dendritic cell numbers in periodontal lesions. Conclusion AAV-mediated Ctsk silencing can simultaneously target both the inflammation and bone resorption associated with periodontitis through its inhibitory effect on immune cells and osteoclast function. Thereby, AAV-sh-Ctsk administration can efficiently protect against periodontal tissue damage and alveolar bone loss, establishing this AAV-mediated local silencing of Ctsk as an important therapeutic strategy for potently treating periodontal disease.