シンポジウム
Recent advancement in Neurochemistry in Asia-Pacific region
―Unexpected function of non-neuronal proteins in nervous system― |
|---|
| 2S2-1
Neuronal innate immunity regulates neural development and function
Hsueh Yi-Ping
Institute of Molecular Biology, Academia Sinica
In the central nervous system, microglial cells are the well-known main immune cells in the brains in response to infection and injury. However, the recent accumulated studies have indicated that neurons also express the key pattern recognition receptors and downstream adaptors for innate immune responses. We are intrigued to explore the functions of innate immune systems in neurons. TLR3, TLR7 and TLR8 are particularly interesting, because these three pattern recognition receptors are able to recognize both pathogenic and endogenous RNAs. Using rodent cortex and hippocampus, we showed that TLR3, TLR7 and TLR8 are expressed in neurons and negatively control dendritic growth in a cell-autonomous manner. Although these TLRs share the similar effect on neuronal morphology, our studies suggested that they use different downstream signaling pathways and effectors to control neuronal growth. Induction of cytokine expression is only required for TLR7 pathway. The comparison of these TLRs will be presented. Besides, the roles of downstream adaptors SARM1 and MYD88 in neurons will also be discussed. Based on our studies, we suggest that neuronal innate immune system recognizes endogenous ligands and restricts dendritic and/or axonal growth. It is critical for neurodevelopment and brain function. Related publications by Hsueh, Y.-P.1. Chen et al. （2011）Sarm1, a negative regulator of innate immunity, interacts with syndecan-2 and regulates neuronal morphology. Journal of Cell Biology 193：769.2. Liu et al. （2013）TLR7 negatively regulates dendrite outgrowth through the Myd88-c-Fos-IL-6 pathway. Journal of Neuroscience 33：11479. 3. Lin et al. （2014）Neuronally-expressed Sarm1 regulates expression of inflammatory and anti-viral cytokines in brains. Innate Immunity 20：161. 4. Lin and Hsueh（2014）Sarm1, a neuronal inflammatory regulator, controls social interaction, associative memory and cognitive flexibility in mice. Brain, Behavior, and Immunity 37：142. 5. Lin et al. （2014）Sarm1 deficiency impairs synaptic function and leads to behavioral deficits, which can be ameliorated by an mGluR allosteric modulator. Frontiers in Cellular Neuroscience 8：87. | | 2S2-2
Microglial ontogeny and functions in shaping embryonic brain circuits
Ginhoux Florent
Singapore Immunology Network, Agency for Science, Technology and Research（A*STAR）
Microglia are the resident macrophage population of the central nervous system（CNS）. Adequate microglial function is crucial for a healthy CNS；microglia are not only the first immune sentinels of infection and inflammation, but are also involved in the maintenance of brain homeostasis. Emerging data are showing new and fundamental roles for microglia in the control of neuronal proliferation and differentiation, as well as in the formation of synaptic connections. In parallel, recent studies on microglial origin indicate that these cells arise very early during development from progenitors in the embryonic yolk sac that produce cells able to persist in the CNS into adulthood. These unique immune cells are thus present at all stages of brain development, including the prenatal stage of neuronal circuit formation, which points to the intriguing possibility that microglia might be involved in development of the CNS. Here, we show that microglia participate to normal embryonic forebrain wiring regulating the progression of dopaminergic axons in the forebrain and the laminar positioning of subsets of interneurons in the neocortex. Our study reveals novel roles for microglia in the normal assembly of brain circuits and raises the possibility that dysregulated embryonic microglial function during pre-natal inflammation could impact forebrain connectivity and could contribute to the etiology of neuropsychiatric disorders. | | 2S2-3
Stress peptides and relapse to reward-seeking
Lawrence Andrew J
University of Melbourne
Relapse and hazardous drinking represent the most difficult clinical problems in treating patients with alcohol use disorders. Increasing our understanding of the brain circuits and chemicals that regulate alcohol intake and relapse offers the potential for more targeted therapeutic approaches to assist in relapse prevention. We have provided evidence for a role of numerous neuropeptides in cue and/or stress induced reward-seeking. This presentation will highlight recent studies on 3 neuropeptide systems, which can act independently and via circuit-level interactions to regulate relapse-like behaviour. Specifically, orexin, corticotropin releasing factor（CRF）and relaxin-3 all act, and appear to also interact, within circuits mediating cue and/or stress-induced relapse-like behaviour. For example, orexin1 receptors in the ventral tegmental area and prelimbic cortex regulate cue-induced reinstatement of alcohol-seeking in rats；relaxin-3 acts upon RXFP3 receptors in the bed nucleus of the stria terminalis to regulate stress-induced reinstatement of alcohol-seeking in rats. | | 2S2-4
Interleukin-1 receptor family proteins function as neuronal synapse organizers
Yoshida Tomoyuki1,2
1Dept of Mol. Neurosci., Grad. Sch. of Med. ＆ Pharma. Sci., Univ. of Toyama，2PRESTO, JST
Interleukin-1（IL-1）family cytokines play crucial roles in immune and inflammatory responses through the activation of a group of structurally related receptors belonging to the IL-1 receptor（IL-1R）family. IL-1R family proteins consist of extracellular three Ig-like domains and a TIR domain in the cytoplasmic portion. By morpholino-mediated gene knockdown screening of causative genes for neurodevelopmental disorders, we identified IL-1 receptor accessory protein-like 1（IL1RAPL1）, a member of IL-1R family, as a key regulator of neuronal synapse formation. IL1RAPL1 expressed in fibroblasts induced excitatory presynaptic differentiation of co-cultured cerebral cortical neurons. Furthermore, we identified presynaptic protein tyrosine phosphatase（PTP）δ as a major IL1RAPL1 interacting protein. Although the presynapse-inducing activity of IL1RAPL1 was completely abolished in PTPδ knockout neurons, the postsynapse-inducing activity of PTPδ was partly suppressed in IL1RAPL1 knockout neurons, suggesting that IL1RAPL1 mediates synapse formation solely through presynaptic PTPδ, while PTPδ organizes postsynaptic differentiation through IL1RAPL1 and other proteins. We found by systematic screening of IL-1 receptor family proteins for synaptogenic activity that IL-1 receptor accessory protein（IL-1RAcP）, a common subunit of receptor complexs for IL-1 cytokines, had strong activity to induce excitatory presynaptic differentiation. IL-1RAcP also required PTPδ to exert the synaptogenic activity. Accordingly, IL-1RAcP knockout mice exhibited decreased spine density in some brain regions as shown in IL1RAPL1 and PTPδ knockout mice. Moreover, X-ray crystallography of PTPδ-IL1RAPL1/IL-1RAcP complex revealed the structural basis of synapse-organizing cell adherent interaction. These results suggest that IL-1 receptor family proteins, IL1RAPL1 and IL-1RAcP function as cell adhesion molecules in the brain to organize neuronal synapse formation. | |
|
|
