@article {2291, title = {knockout in excitatory neurons impairs postnatal synapse maturation and increases the repressive histone modification H3K27me3.}, journal = {Elife}, volume = {11}, year = {2022}, month = {2022 May 23}, abstract = {

Two epigenetic pathways of transcriptional repression, DNA methylation and polycomb repressive complex 2 (PRC2), are known to regulate neuronal development and function. However, their respective contributions to brain maturation are unknown. We found that conditional loss of the de novo DNA methyltransferase in mouse excitatory neurons altered expression of synapse-related genes, stunted synapse maturation, and impaired working memory and social interest. At the genomic level, loss of abolished postnatal accumulation of CG and non-CG DNA methylation, leaving adult neurons with an unmethylated, fetal-like epigenomic pattern at ~222,000 genomic regions. The PRC2-associated histone modification, H3K27me3, increased at many of these sites. Our data support a dynamic interaction between two fundamental modes of epigenetic repression during postnatal maturation of excitatory neurons, which together confer robustness on neuronal regulation.

}, keywords = {Animals, Brain, Disease Models, Animal, DNA Methyltransferase 3A, Histone Code, Histones, Mice, Mice, Knockout, Neurons, Polycomb Repressive Complex 2, Synapses}, issn = {2050-084X}, doi = {10.7554/eLife.66909}, author = {Li, Junhao and Pinto-Duarte, Ant{\'o}nio and Zander, Mark and Cuoco, Michael S and Lai, Chi-Yu and Osteen, Julia and Fang, Linjing and Luo, Chongyuan and Lucero, Jacinta D and Gomez-Castanon, Rosa and Nery, Joseph R and Silva-Garcia, Isai and Pang, Yan and Sejnowski, Terrence J and Powell, Susan B and Ecker, Joseph R and Mukamel, Eran A and Behrens, M Margarita} } @article {1807, title = {Impairments in remote memory caused by the lack of Type 2 IP3 receptors}, journal = {Glia}, volume = {67}, year = {2019}, pages = {1976-1989}, abstract = {

Abstract The second messenger inositol 1,4,5-trisphosphate (IP3) is paramount for signal transduction in biological cells, mediating Ca2+ release from the endoplasmic reticulum. Of the three isoforms of IP3 receptors identified in the nervous system, Type 2 (IP3R2) is the main isoform expressed by astrocytes. The complete lack of IP3R2 in transgenic mice was shown to significantly disrupt Ca2+ signaling in astrocytes, while leaving neuronal intracellular pathways virtually unperturbed. Whether and how this predominantly nonneuronal receptor might affect long-term memory function has been a matter of intense debate. In this work, we found that the absence of IP3R2-mediated signaling did not disrupt normal learning or recent (24{\textendash}48 h) memory. Contrary to expectations, however, mice lacking IP3R2 exhibited remote (2{\textendash}4 weeks) memory deficits. Not only did the lack of IP3R2 impair remote recognition, fear, and spatial memories, but it also prevented naturally occurring post-encoding memory enhancements consequent to memory consolidation. Consistent with the key role played by the downscaling of synaptic transmission in memory consolidation, we found that NMDAR-dependent long-term depression was abnormal in ex vivo hippocampal slices acutely prepared from IP3R2-deficient mice, a deficit that could be prevented upon supplementation with D-serine - an NMDA-receptor co-agonist whose synthesis depends upon astrocytes{\textquoteright} activity. Our results reveal that IP3R2 activation, which in the brain is paramount for Ca2+ signaling in astrocytes, but not in neurons, can help shape brain plasticity by enhancing the consolidation of newly acquired information into long-term memories that can guide remote cognitive behaviors.

}, keywords = {astrocyte, Behavior, Ca2+ signaling, long-term memory, synaptic plasticity}, doi = {https://doi.org/10.1002/glia.23679}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/glia.23679}, author = {Pinto-Duarte, Ant{\'o}nio and Roberts, Amanda J. and Ouyang, Kunfu and Sejnowski, Terrence J.} } @article {1684, title = {Evidence for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.}, journal = {Proc Natl Acad Sci U S A}, volume = {114}, year = {2017}, month = {2017 01 24}, pages = {E610-E618}, abstract = {

The signaling mechanisms that choreograph the assembly of the highly asymmetric pre- and postsynaptic structures are still poorly defined. Using synaptosome fractionation, immunostaining, and coimmunoprecipitation, we found that Celsr3 and Vangl2, core components of the planar cell polarity (PCP) pathway, are localized at developing glutamatergic synapses and interact with key synaptic proteins. Pyramidal neurons from the hippocampus of Celsr3 knockout mice exhibit loss of \~{}50\% of glutamatergic synapses, but not inhibitory synapses, in culture. Wnts are known regulators of synapse formation, and our data reveal that Wnt5a inhibits glutamatergic synapses formed via Celsr3. To avoid affecting earlier developmental processes, such as axon guidance, we conditionally knocked out Celsr3 in the hippocampus 1 week after birth. The CA1 neurons that lost Celsr3 also showed a loss of \~{}50\% of glutamatergic synapses in vivo without affecting the inhibitory synapses assessed by miniature excitatory postsynaptic current (mEPSC) and electron microscopy. These animals displayed deficits in hippocampus-dependent behaviors in adulthood, including spatial learning and memory and fear conditioning. In contrast to Celsr3 conditional knockouts, we found that the conditional knockout of Vangl2 in the hippocampus 1 week after birth led to a large increase in synaptic density, as evaluated by mEPSC frequency and spine density. PCP signaling is mediated by multiple core components with antagonizing functions. Our results document the opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation.

}, keywords = {Animals, Behavior, Animal, Cadherins, Cell Polarity, Cells, Cultured, Excitatory Postsynaptic Potentials, Glutamic Acid, Hippocampus, Locomotion, Male, Maze Learning, Mice, Knockout, Nerve Tissue Proteins, Pyramidal Cells, Receptors, Cell Surface, Synapses, Wnt-5a Protein}, issn = {1091-6490}, doi = {10.1073/pnas.1612062114}, author = {Thakar, Sonal and Wang, Liqing and Yu, Ting and Ye, Mao and Onishi, Keisuke and Scott, John and Qi, Jiaxuan and Fernandes, Catarina and Han, Xuemei and Yates, John R and Berg, Darwin K and Zou, Yimin} } @article {1688, title = {Subiculum neurons map the current axis of travel.}, journal = {Nat Neurosci}, volume = {20}, year = {2017}, month = {2017 02}, pages = {170-172}, abstract = {

Flexible navigation demands knowledge of boundaries, routes and their relationships. Within a multi-path environment, a subpopulation of subiculum neurons robustly encoded the axis of travel. The firing of axis-tuned neurons peaked bimodally, at head orientations 180{\textdegree} apart. Environmental manipulations showed these neurons to be anchored to environmental boundaries but to lack axis tuning in an open arena. Axis-tuned neurons thus provide a powerful mechanism for mapping relationships between routes and the larger environmental context.

}, keywords = {Action Potentials, Animals, Brain Mapping, Hippocampus, Male, Neurons, Orientation, Rats, Sprague-Dawley, Space Perception}, issn = {1546-1726}, doi = {10.1038/nn.4464}, author = {Olson, Jacob M and Tongprasearth, Kanyanat and Nitz, Douglas A} } @article {153, title = {Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila.}, journal = {Science}, volume = {277}, year = {1997}, month = {1997 Aug 8}, pages = {834-6}, abstract = {

Naturally occuring polymorphisms in behavior are difficult to map genetically and thus are refractory to molecular characterization. An exception is the foraging gene (for), a gene that has two naturally occurring variants in Drosophila melanogaster food-search behavior: rover and sitter. Molecular mapping placed for mutations in the dg2 gene, which encodes a cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG). Rovers had higher PKG activity than sitters, and transgenic sitters expressing a dg2 complementary DNA from rover showed transformation of behavior to rover. Thus, PKG levels affected food-search behavior, and natural variation in PKG activity accounted for a behavioral polymorphism.

}, keywords = {Animals, Animals, Genetically Modified, Cyclic GMP, Cyclic GMP-Dependent Protein Kinases, Drosophila melanogaster, Feeding Behavior, Genes, Insect, Larva, Phenotype, Polymorphism, Genetic, Signal Transduction}, issn = {0036-8075}, author = {Osborne, K A and Robichon, A and Burgess, E and Butland, S and Shaw, R A and Coulthard, A and Pereira, H S and Greenspan, R J and Sokolowski, M B} }