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.

• MeSH
• demence epidemiologie   genetika   psychologie   MeSH
• dospělí MeSH
• fenotyp MeSH
• jaderné proteiny genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikrofilamentové proteiny genetika   MeSH
• myši knockoutované MeSH
• myši MeSH
• neuroplasticita genetika   MeSH
• paměť fyziologie   MeSH
• posttraumatická stresová porucha komplikace   epidemiologie   genetika   MeSH
• rizikové faktory MeSH
• stárnutí genetika   fyziologie   MeSH
• studie případů a kontrol MeSH
• věk při počátku nemoci MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Long-term potentiation (LTP) in the rat hippocampus is the most extensively studied cellular model for learning and memory. Induction of classical LTP involves an NMDA-receptor- and calcium-dependent increase in functional synaptic AMPA receptors, mediated by enhanced recycling of internalized AMPA receptors back to the postsynaptic membrane. Here we report a physiologically relevant NMDA-receptor-independent mechanism that drives increased AMPA receptor recycling and LTP. This pathway requires the metabotropic action of kainate receptors and activation of G protein, protein kinase C and phospholipase C. Like classical LTP, kainate-receptor-dependent LTP recruits recycling endosomes to spines, enhances synaptic recycling of AMPA receptors to increase their surface expression and elicits structural changes in spines, including increased growth and maturation. These data reveal a new and, to our knowledge, previously unsuspected role for postsynaptic kainate receptors in the induction of functional and structural plasticity in the hippocampus.

• MeSH
• AMPA receptory metabolismus   MeSH
• dendritické trny metabolismus   MeSH
• dlouhodobá potenciace fyziologie   MeSH
• endozomy metabolismus   MeSH
• fosfolipasy typu C metabolismus   MeSH
• hipokampus fyziologie   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• neurony metabolismus   fyziologie   MeSH
• proteinkinasa C metabolismus   MeSH
• proteiny vázající GTP metabolismus   MeSH
• receptory kyseliny kainové fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Photoactivation of caged biomolecules has become a powerful approach to study cellular signalling events. Here we report a method for anchoring and uncaging biomolecules exclusively at the outer leaflet of the plasma membrane by employing a photocleavable, sulfonated coumarin derivative. The novel caging group allows quantifying the reaction progress and efficiency of uncaging reactions in a live-cell microscopy setup, thereby greatly improving the control of uncaging experiments. We synthesized arachidonic acid derivatives bearing the new negatively charged or a neutral, membrane-permeant coumarin caging group to locally induce signalling either at the plasma membrane or on internal membranes in β-cells and brain slices derived from C57B1/6 mice. Uncaging at the plasma membrane triggers a strong enhancement of calcium oscillations in β-cells and a pronounced potentiation of synaptic transmission while uncaging inside cells blocks calcium oscillations in β-cells and causes a more transient effect on neuronal transmission, respectively. The precise subcellular site of arachidonic acid release is therefore crucial for signalling outcome in two independent systems.

• MeSH
• beta-buňky metabolismus   účinky záření   MeSH
• buněčná membrána metabolismus   účinky záření   MeSH
• HeLa buňky MeSH
• kumariny chemie   metabolismus   MeSH
• kyselina arachidonová chemie   metabolismus   MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neurony metabolismus   účinky záření   MeSH
• světlo MeSH
• vápník metabolismus   MeSH
• vápníková signalizace účinky záření   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH