Impairment of long-term depression induced by chronic brain inflammation in rats Sun Seek Min a,1 , Hui Yan Quan a,1 , Jinhua Ma b , Ki Ho Lee c , Seung Keun Back d , Heung Seek Na d , Seung Ho Han a , Jae-Yong Yee a , Chan Kim a , Jung-Soo Han b , Geun Hee Seol a,e, * a Department of Physiology and Biophysics, Eulji University School of Medicine, Daejeon 301-832, South Korea b Department of Biological Sciences & Center for Geriatric Neuroscience Research, IBST, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul 143-701, South Korea c Department of Biochemistry and Molecular Biology, Eulji University School of Medicine, Daejeon 301-832, South Korea d Department of Physiology, Korea University School of Medicine, Seoul 136-705, South Korea e Department of Basic Nursing Science, Korea University School of Nursing, Anam-Dong, Seongbuk-Gu, Seoul 136-713, South Korea article info Article history: Received 15 March 2009 Available online 31 March 2009 Keywords: Neuroinflammation Long-term depression NMDAR-dependent LTD NMDAR-independent LTD Dementia Hippocampus abstract Although deficits in synaptic plasticity have been identified in aged or neuroinflamed animals with mem- ory impairments, few studies have examined the cellular basis of plasticity in such animals. Here, we examined whether chronic neuroinflammation altered long-term depression (LTD) and studied the underlying mechanism of LTD impairment by neuroinflammation. Chronic neuroinflammation was induced by administration of lipopolysaccharide (LPS) to the fourth ventricle. Excitatory postsynaptic potentials were recorded extracellularly in the rat hippocampal CA1 area to examine alterations in syn- aptic plasticity. Chronic administration of LPS induced remarkable memory impairment in the Morris water maze test. N-methyl-D-aspartate receptor (NMDAR)-dependent LTD was almost absent in LPS- infused animals. The AMPA receptor (AMPAR)-mediated synaptic response was reduced in the LPS- infused group. These results suggest that reduction in NMDAR-dependent LTD might arise because of alterations in postsynaptic AMPARs as well as NMDARs and that such changes may be present in mild and early forms of Alzheimer-type dementia. Ó 2009 Elsevier Inc. All rights reserved. Introduction Chronic neuroinflammation plays an essential role in the path- ogenesis of Alzheimer’s disease (AD) [1–3]. Recent reports suggest that AD and other forms of dementia arise because of pathological processes in which synaptic loss and dysfunction begin several years prior to severe neuronal loss [4]. A number of experiments have now consistently reported that chronic neuroinflammation can be reproduced in rats by infusion of lipopolysaccharide (LPS) into the fourth ventricle [5–8]. LPS activates microglia to initiate a series of inflammation-induced changes within the hippocampus and entorhinal cortex [5,6]. The N-methyl-D-aspartate receptors (NMDARs) play an impor- tant role in modulation of excitatory synaptic transmission be- cause of high permeability to calcium ions and an ability to activate downstream calcium-dependent signal transduction pro- cesses. Because of the high Ca 2+ permeability, activation of NMDARs is often the first event in glutamate-induced neuronal in- jury [9]. The AMPA receptors (AMPARs) are the other major sub- type of ligand-gated ionotropic glutamate receptors. AMPARs are essential for synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), both of which are mecha- nisms involved in learning, memory, and experience-dependent plasticity [10,11]. Although deficits in synaptic plasticity have been identified in neuroinflamed animals with memory impairments [6], few studies have examined the cellular basis for plasticity in such animals. Here, we examine whether chronic neuroinflammation within the hippocampus alters NMDAR-dependent and NMDAR-indepen- dent LTD in Schaffer collateral/commissural-CA1 synapses, and investigate alterations in NMDAR- and AMPAR-mediated re- sponses induced by chronic LPS infusion. Materials and methods Fourteen male Fisher-344 rats (SLC Inc., Shizuoka, Japan) were housed singly in colony rooms with a 12 h light–dark cycle (lights on at 7 a.m.). Animal experiments were conducted in accordance with approved institutional animal care procedures. Rats were 0006-291X/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2009.03.133 * Corresponding author. Address: Department of Basic Nursing Science, Korea University School of Nursing, Anam-Dong, Seongbuk-Gu, Seoul 136-713, South Korea. Fax: +82 02 927 4676. E-mail address: ghseol@korea.ac.kr (G.H. Seol). 1 These authors contributed equally to this work. Biochemical and Biophysical Research Communications 383 (2009) 93–97 Contents lists available at ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc