Epigenetic control of BDNF gene expression and neural plasticity

Abstracts SY2-C3-4 The human amygdala in social cognition Ralph Adolphs California Institute of Technology, USA The amygdala has long been linked to both social behavior and emotion. We have carried out a series of studies in human patients with focal amygdala lesions, investigating their decision-making, emotion recognition, and social cognition. We have found that the human amygdala is important for a variety of social judgments from faces, including judgments of trustworthiness and of fear. Recently, we found that the amygdala’s role in fear recognition resulted from a mechanism whereby it directs gaze and attention to socially salient regions of the face: a patient with amygdala lesions was impaired in looking at the eye region of faces. We have now begun to translate some of these studies into the real social world. For instance, patients with amygdala lesions are also impaired at making eye contact with real people, and in social interactions, they do not appear to have a sense of personal space. These findings are being followed up with a variety of additional approaches, including fMRI studies and studies of people with autism. doi:10.1016/j.neures.2009.09.1588

SY2-C3-5 The roles of hormone-dependent neurons in the amygdala as they regulate social behaviors Donald Pfaff The Rockefeller University, USA Estrogens (E) are bound to their cognate receptors (ERs) in the nuclei of many neurons in the amygdala, particularly the medial subdivision. This is the same part of the amygdala that receives significant input from the vomeronasal/accessory olfactory bulb system for communicating pheromonal information. Importantly, oxytocin, synthesized in the paraventricular nucleus of the hypothalamus, is bound by OT receptors (OTR) in the amygdala. Our experiments used microinjections into the amygdala of biodegradable microparticles bearing antisense DNA moieties in order to interrupt expression of genes that support this E/OT-dependent set of mechanisms. Our results showed that a 4-gene micronet is necessary for normal (olfactory signaled) social recognition: genes for ER-alpha, ER-beta, OT and OTR. These experiments were performed in female mice. We further hypothesize that males are susceptible to abnormalities of social recognition and interaction due to social anxiety consequent to androgen receptor (AR) dependent signaling in CNS arousal pathways. Such an testosterone/AR effect could account for the predominance of males in the incidence of autism. doi:10.1016/j.neures.2009.09.1589

SY2-D1-1 Imprinting in neuron Tatsuya Kishino Div. of Func. Genom., Ctr. for Front. Sci., Nagasaki University, Nagasaki, Japan Genomic imprinting in mammals describes the situation where there is nonequivalence in expression between the maternal and paternal alleles. Such parental-origin-specific gene regulation is caused by epigenetic modifications that occur during gametogenesis without any nucleic acid changes. Most imprinted genes display parent-origin-specific gene expression in tissues where they are transcribed, however some genes are imprinted in a tissue-specific manner. Genes that show brain-specific imprinting present a unique opportunity to study the process of imprinting during tissue differentiation. Here we show the systematic study of brain-cell-lineage-specific imprinting using a primary brain cell culture system; neuron-specific imprinting in Ube3a,and Grb10, and neuron-specific non-imprinting, Igf2r. Such brain-cell-lineage-specific imprinting was associated with cell-specific histone modificaitons by Polycomb group (PcG) protein, sometimes with their reciprocally imprinted antisense non-coding RNAs. Our data suggest that tissue-specific imprinting might be directly regulated by the repressive chromatin mediated by PcG complex during development. doi:10.1016/j.neures.2009.09.1590

SY2-D1-2 Epigenetic mechanism conferring astrocytic potential on neural precursor cells Tsukasa Sanosaka 1 , Masakazu Namihira 1 , Jun Kohyama 1 , Katsunori Semi 1 , Benjamin Deneen 2 , Tetsuya Taga 3 , kinichi Nakashima 1 1 Molecular Neuroscience, Nara Institute of Science and Technology, Nara, Japan; 2 Division of Biology, California Institute of Technology, CA, USA; 3 Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

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During mid-gestation, mammalian neural precursor cells (NPCs) differentiate only into neurons. Generation of astrocytes is prevented at this stage, because astrocyte-specific gene promoters are methylated. How the subsequent switch from suppression to expression of astrocytic genes occurs had been unknown. We here show that, in mid-gestationanl telencephalon, committed neuronal precursors that express Notch ligand can activate Notch signaling in adjacent neural precursor cells (NPCs), leading to NFI-mediated promoter demethylation, and thus to expression of astrocyte-specific genes. These findings provide a mechanistic explanation for why neurons come first: committed neuronal precursors and young neurons potentiate remaining NPCs to differentiate into the next cell lineage, astrocytes. doi:10.1016/j.neures.2009.09.1591

SY2-D1-3 Epigenetic control of BDNF gene expression and neural plasticity Masaaki Tsuda Dept Mol Neurobiol, Grad Sch Med & Pharm, Univ of Toyama, Japan Brain-derived neurotrophic factor (BDNF) is playing a fundamental role in controlling neural plasticity like memory consolidation. Focusing on the BDNF gene promoter I and IV (BDNF-PI and -PIV), both of which respond to calcium (Ca2+ ) signals, we investigated molecular mechanisms for controlling BDNF gene expression in terms of epigenetics. Both the BDNF-PI and -PIV were demethylated in rat cortical neurons in culture. The BDNF-PI was constitutively repressed by neuralrestrictive silencing protein (NRSF) from far downstream, the repression by which was released by Ca2+ signals. Acetylation of histones on BDNF-PI was markedly induced by Ca2+ signals evoked via depolarization. The BDNF exon I–IX but not IV–IX mRNA expression remained elevated even after depolarization was removed, which might be related to acetylation of histones. On the other hand, stimulation of G-protein-coupled receptors effectively effectively induced BDNF exon IV–IX mRNA expression through NMDA receptors, a typical activity-dependent gene expression in neurons. doi:10.1016/j.neures.2009.09.1592

SY2-D1-4 Epigenetic regulation in the neuronal plasticity in chronic pain Hiroshi Ueda Div Mol Pharmacol Neurosci, Nagasaki Univ, Nagasaki, Japan Peripheral nerve injury causes a chronic neuropathic pain, which is often resistant to morphine. A variety of changes in gene expression in primary afferent are known to play a key role in the neuronal plasticity underlying neuropathic pain. One of the characteristic alterations is a long-lasting down-regulation of pain-related genes such as ␮ opioid receptor and voltage-gated ion channels, which are known to contain neuron-restrictive silencer element (NRSE). Here we found that nerve injury up-regulates neuron-restrictive silencer factor (NRSF) expression in dorsal root ganglion neuron. We further show that NRSF induces epigenetic silencing of NRSEcontaining pain-related genes after nerve injury. Finally, we demonstrate that a lack of peripheral morphine analgesia in neuropathic pain is recovered by antisenseknockdown of NRSF gene. Taken together, these data suggest that NRSF, a master transcriptional suppressor, causes a long-lasting neuronal plasticity through epigenetic mechanisms in neuropathic pain. doi:10.1016/j.neures.2009.09.1593

SY2-D2-1 Transcranial optogenetic mapping of the mouse motor cortex Masanori Matsuzaki University of Tokyo, Japan We developed a method that uses Channelrhodopsin-2 (ChR2) for transcranial optogenetic stimulation. This method is based on scanning a light beam over the brain, thereby photostimulating ChR2-expressing neurons in intact mice. We applied this technique to the motor cortex of transgenic mice expressing ChR2 in cortical pyramidal cells. Photostimulation induced limb movements that were time-locked with millisecond precision and could be induced at frequencies up to 20 Hz. By scanning this light beam, we could map the distribution of neurons associated with limb movement. With this approach we could simultaneously define motor maps controlling two limbs and could reproducibly generate such cortical motor maps over periods of weeks. This method allows non-invasive mapping of brain circuitry in living animals and could help define the connection between behavior and brain circuitry. doi:10.1016/j.neures.2009.09.1594