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Koga, K.,Descalzi, G.,Chen, T.,Ko, H.G.,Lu, J.,Li, S.,Son, J.,Kim, T.,Kwak, C.,Huganir, Richard L.,Zhao, M.g.,Kaang, B.K.,Collingridge, Graham L.,Zhuo, M. Cell Press 2015 Neuron Vol.85 No.2
Chronic pain can lead to anxiety and anxiety can enhance the sensation of pain.@?Unfortunately, little is known about the synaptic mechanisms that mediate these re-enforcing interactions. Here we characterized two forms of long-term potentiation (LTP) in the anterior cingulate cortex (ACC); a presynaptic form (pre-LTP) that requires kainate receptors and a postsynaptic form (post-LTP) that requires N-methyl-D-aspartate receptors. Pre-LTP also involves adenylyl cyclase and protein kinase A and is expressed via a mechanism involving hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Interestingly, chronic pain and anxiety both result in selective occlusion of pre-LTP. Significantly, microinjection of the HCN blocker ZD7288 into the ACC in vivo produces both anxiolytic and analgesic effects. Our results provide a mechanism by which two forms of LTP in the ACC may converge to mediate the interaction between anxiety and chronic pain.
Na, Y.,Park, S.,Lee, C.,Kim, D.K.,Park, J.M.,Sockanathan, S.,Huganir, R.L.,Worley, P.F. Cell Press 2016 Neuron Vol.91 No.3
<P>The immediate early gene Arc (also Arg3.1) produces rapid changes in synaptic properties that are linked to de novo translation. Here we develop a novel translation reporter that exploits the rapid maturation and 'flash' kinetics of Gaussia luciferase (Gluc) to visualize Arc translation. Following glutamate stimulation, discrete Arc-Gluc bioluminescent flashes representing sites of de novo translation are detected within 15 s at distributed sites in dendrites, but not spines. Flashes are episodic, lasting similar to 20 s, and may be unitary or repeated at similar to minute intervals at the same sites. Analysis of flash amplitudes suggests they represent the quantal product of one or more polyribosomes, while inter-flash intervals appear random, suggesting they arise from a stochastic process. Surprisingly, glutamate-induced translation is dependent on Arc open reading frame. Combined observations support a model in which stalled ribosomes are reactivated to rapidly generate Arc protein.</P>
Lim, Chae-Seok,Kang, Xi,Mirabella, Vincent,Zhang, Huaye,Bu, Qian,Araki, Yoichi,Hoang, Elizabeth T.,Wang, Shiqiang,Shen, Ying,Choi, Sukwoo,Kaang, Bong-Kiun,Chang, Qiang,Pang, Zhiping P.,Huganir, Richar Cold Spring Harbor Laboratory Press 2017 Genes & development Vol.31 No.6
<P>Rapid advances in genetics are linking mutations on genes to diseases at an exponential rate, yet characterizing the gene mutation-cell behavior relationships essential for precision medicine remains a daunting task. More than 350 mutations on small GTPase BRaf are associated with various tumors, and similar to 40 mutations are associated with the neurodevelopmental disorder cardio-facio-cutaneous syndrome (CFC). Wedeveloped a fast cost-effective lentivirus-based rapid gene replacement method to interrogate the physiopathology of BRaf and similar to 50 disease-linked BRaf mutants, including all CFC-linked mutants. Analysis of simultaneous multiple patch-clamp recordings from 6068 pairs of rat neurons with validation in additional mouse and human neurons and multiple learning tests from 1486 rats identified BRaf as the key missing signaling effector in the common synaptic NMDA-R-CaMKII-SynGap-Ras-BRaf-MEK-ERK transduction cascade. Moreover, the analysis creates the original big data unveiling three general features of BRaf signaling. This study establishes the first efficient procedure that permits large-scale functional analysis of human disease-linked mutations essential for precision medicine.</P>
Wang, Shih-Hsiu J.,Celic, Ivana,Choi, Se-Young,Riccomagno, Martin,Wang, Qiang,Sun, Lu O.,Mitchell, Sarah P.,Vasioukhin, Valera,Huganir, Richard L.,Kolodkin, Alex L. Society for Neuroscience 2014 The Journal of neuroscience Vol.34 No.38
<P>Most excitatory synapses in the mammalian brain are formed on dendritic spines, and spine density has a profound impact on synaptic transmission, integration, and plasticity. Membrane-associated guanylate kinase (MAGUK) proteins are intracellular scaffolding proteins with well established roles in synapse function. However, whether MAGUK proteins are required for the formation of dendritic spines <I>in vivo</I> is unclear. We isolated a novel <I>disc large-5</I> (<I>Dlg5</I>) allele in mice, <I>Dlg5</I><SUP>LP</SUP>, which harbors a missense mutation in the DLG5 SH3 domain, greatly attenuating its ability to interact with the DLG5 GUK domain. We show here that DLG5 is a MAGUK protein that regulates spine formation, synaptogenesis, and synaptic transmission in cortical neurons. DLG5 regulates synaptogenesis by enhancing the cell surface localization of <I>N</I>-cadherin, revealing a key molecular mechanism for regulating the subcellular localization of this cell adhesion molecule during synaptogenesis.</P>