Visit Dr. Xiong's laboratory
Durham Research Center, Room 8013
UNMC Today, May 2, 2011
Keywords: voltage-gated K channels, NMDA receptors, synaptic transmission and plasticity, neuroinflammation, neuromodulation, learning and memory, HIV-1-associated neurological disorders
The research focus in the Neurophysiology Laboratory is to study cellular and molecular mechanisms underlying the pathogenesis of neurodegenerative disorders including HIV-1-associated dementia (HAD) and Alzheimer’s disease (AD) and to identify potential target(s) for development of therapeutic strategies.
Specifically, we are interested in the role played by mononuclear phagocytes (MPs, brain macrophages and microglia) in HAD/AD pathogenesis, focusing on how the soluble factors (e.g. cytokines), secreted by HIV-1-infected or beta amyloid (Aβ)-stimulated MPs, alter cellular and synaptic physiology resulting in neural dysfunction and degeneration.
One particular interest is to study how MP secretions influence neuronal voltage-gated K+ (Kv) channels leading to neuronal degeneration and resultant cognitive decline as seen in HAD/AD patients. Studies from other laboratories have shown that neuronal K+ currents decrease during learning and animal mutants with Kv channel dysfunction exhibit learning and memory deficits. We hypothesize that HIV-1-infected or Aβ-stimulated MPs decrease neuronal excitability by enhancing outward K+ current, leading to neuronal dysfunction/degeneration and cognitive impairment. To test this hypothesis, we are studying the effects of MP secretions on neuronal outward K+ current and the protective effects of Kv channel blockers on neurocognitive processes in animal models.
Another particular interest is to examine the role of extrasynaptic NMDA receptors (NMDAR) and their signal transduction pathways in MP-associated neurodegeneration. This study is based on recent observations that the location of NMDARs makes the key difference, survival promoting signals derive from synaptic NMDARs, which consist of predominant NR2A-containing NMDARs (NR2ARs); whereas, a cell-death signal comes from extrasynaptic NMDARs, which contain mostly NR2BRs. We hypothesize that HIV-1-infected or Aβ-stimulated MPs elicit activation of extrasynaptic NR2BRs and their signal transduction pathways affecting neuronal and cognitive function. Our goals are to determine the role played by synaptic and extrasynaptic NMDARs in the pathogenesis of neurodegenerative disorders and to identify the target(s) for therapeutic interventions.
Zhou Y, Tang H, Liu J, Dong J, Xiong H Chemokine CCL2 modulation of neuronal excitability and synaptic transmission in rat hippocampal slices. J. Neurochem. 116(3):406-14, 2011
Zhang J, Liu J, Katafiasz B, Fox H, Xiong H. HIV-1 gp120-Induced Axonal Injury Detected by Accumulation of β-Amyloid Precursor Protein in Adult Rat Corpus Callosum. J. NeuroImmune Pharmacol., 2011 (in press)
Jing T, Wu L, Borgmann K, Surendran S, Ghorpade A, Liu J, Xiong H. Soluble factors from IL-1β-stimulated astrocytes activate NR1a/NR2B receptors: Implications for HIV-1-induced neurodegeneration. Biochem Biophys Res Commun.12:402(2):241-6 2010
Rump TJ, Muneer PM, Szlachetka AM, Lamb A, Haorei C, Alikunju S, Xiong H, Keblesh J, Liu J, Zimmerman MC, Jones J, Donohue TM Jr, Persidsky Y, Haorah J. Acetyl-L-carnitine protects neuronal function from alcohol-induced oxidative damage in the brain. Free Radic Biol Med. 2010 Nov 30;49(10):1494-504
Peng F, Yao H, Bai X, Zhu X, Reiner BC, Beazely M, Funa K, Xiong H, Buch S. Platelet-derived growth factor-mediated induction of the synaptic plasticity gene Arc/Arg3.1. J Biol Chem. 2010 Jul 9;285(28):21615-24
Reiner BC, Keblesh JP, Xiong H. Methamphetamine abuse, HIV infection, and neurotoxicity. Int J Physiol Pathophysiol Pharmacol. 2009 September 25; 1(2): 162–179
Kiyota T, Yamamoto M, Xiong H, Lambert MP, Klein WL, Gendelman HE, Ransohoff RM, Ikezu T. CCL2 accelerates microglia-mediated Abeta oligomer formation and progression of neurocognitive dysfunction. PLoS One. 2009; 4(7): e6197
Keblesh JP, Dou H, Gendelman HE, Xiong H. 4-Aminopyridine Improves Spatial Memory in a Murine Model of HIV-1 Encephalitis.J Neuroimmune Pharmacol. 2009 Sep;4(3):317-27.
Tang H, Lu D, Pan R, Qin X, Xiong H, Dong J. Curcumin improves spatial memory impairment induced by human immunodeficiency virus type 1 glycoprotein 120 V3 loop peptide in rats. Life Sci. 85(1-2):1-10, 2009
Gendelman, HE, Ding, SY, Gong, N, Liu, J, Ramirez, S, Persidsky, Y, Wang, T, Volsky, DJ, Xiong, H. Monocyte Chemotactic Protein-1 Regulates Voltage-Gated K+ Channels and Macrophage Transmigration. J. Neuroimmune Pharmcol. 4(1):47-59, 2009
Keblesh J, Hu DH, Xiong H. Voltage-gated Potassium Channels in Human Immunodeficiency Virus Type-1 (HIV-1)-associated Neurocognitive Disorders. J Neuroimmune Pharm. 4(1):60-70, 2009
Xiong H, Chang SL, Buch S, Roy S, Ho WZ. SNIP Members in a Recent International Conference: World Summit of Antivirals. J Neuroimmune Pharm. 4(1):4-6, 2009Additional publications on PubMed