Acute exposure to CXC chemokine ligand 10, but not its chronic astroglial production, alters synaptic plasticity in mouse hippocampal slices Roman Vlkolinsky ´, George R. Siggins, Iain L. Campbell, Thomas Krucker * Department of Neuropharmacology, CVN-12, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA Received 5 September 2003; received in revised form 12 January 2004; accepted 12 January 2004 Abstract Brain levels of CXC chemokine ligand 10 (CXCL10) are elevated in a number of neuropathological conditions. To determine its impact on neuronal function, we measured synaptic transmission and plasticity in hippocampal slices prepared from transgenic (TG) mice with chronic astroglial production of CXCL10. We also tested the acute effect of recombinant CXCL10 applied to slices from normal C57Bl/6J mice, CXCL10 TG mice and CXCR3 knock out (KO) mice. Chronic production of CXCL10 did not alter synaptic plasticity. By contrast, exogenous CXCL10 (10 ng/ml) significantly inhibited long-term potentiation (LTP) in slices from normal C57Bl/6J mice and CXCL10 TG. The effect was probably receptor-mediated because CXCL10-induced inhibition of LTP was not observed in CXCR3 KO mice. Our findings suggest that acute exposure to CXCL10 alters synaptic plasticity via CXCR3 in mouse hippocampus. D 2004 Elsevier B.V. All rights reserved. Keywords: Alzheimer’s disease; CXCR3; IP-10; Neurodegeneration; NeuroAIDS; Paired-pulse facilitation 1. Introduction The chemokines classically have been considered as mediators of inflammatory responses, with a pivotal role in chemotaxis of leukocytes (Rollins, 1997). There is evi- dence that chemokines and their receptors in the CNS are also involved in complex physiological interactions during neurogenesis (Asensio and Campbell, 1999; Bajetto et al., 2001; Lu et al., 2002; Tsai et al., 2002; Zhu et al., 2002b), in mechanisms of cell – viral interactions (Kaul et al., 2001; Langford et al., 2002; Sanders et al., 2000) and in regulation of neuronal function (Bajetto et al., 2001; Giovannelli et al., 1998; Meucci et al., 1998; Puma et al., 2001). The CXC chemokine ligand 10 (CXCL10), previously known as interferon-g inducible protein 10 (IP-10), is a member of the non-ELR chemokine family. It is a secreted polypeptide with a molecular mass of 8.7 kDa and chemo- attractant activity for several subtypes of leukocytes, includ- ing Th1 lymphocytes, natural killer cells, macrophages and eosinophils (Cross and Woodroofe, 1999; Jinquan et al., 2000; Kolb et al., 1999; Loetscher et al., 1996; Taub et al., 1993). In the brain CXCL10 is produced under pathological conditions by astrocytes, microglia and also by neurons (Asensio et al., 1999; Kutsch et al., 2000; Ransohoff et al., 1993; Simpson et al., 2000; Wang et al., 1998). Clinically, CXCL10 has been implicated in neuropatho- genesis, because CNS tissue levels and cerebro-spinal fluid concentrations of this chemokine were repeatedly found to be elevated in a number of neurological disorders such as multiple sclerosis, Alzheimer’s disease, and HIV-associated dementia (HAD) (Franciotta et al., 2001; Kieseier et al., 2002; Kolb et al., 1999; Sorensen et al., 1999). In Alzheim- er’s disease CXCL10 expression was localized in the disease-affected areas (Xia et al., 2000), and in HAD a significant correlation has been reported between the CXCL10 brain levels and the progression of neuropsychi- atric impairment (Kolb et al., 1999). The elevation of 0165-5728/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2004.01.011 Abbreviations: ACSF, artificial cerebrospinal fluid; CNS, central nervous system; CXCL10, CXC chemokine ligand 10; CXCR3, membrane receptor for CXCL10; EAE, experimental autoimmune encephalitis; ELR, glutamic acid-leucine-arginine containing motif; ERK, extracellular-signal regulated kinase; fEPSP, field excitatory postsynaptic potential; GFAP, glial fibrillary acidic protein; HAD, HIV-associated dementia; HFS, high frequency stimulation; I – O, input – output; IPI, inter-pulse interval; KO, knock out; LTP, long-term potentiation; MAPK, mitogen-activated protein kinase; PPF, paired-pulse facilitation; PPI, paired-pulse inhibition; PI3K, phosphatidylinositol 3-kinase; PS, population spike; PTP, post-tetanic potentiation; pV, presynaptic fiber volley; SI, stimulus intensity; Src, non- receptor tyrosine kinase; TG, transgenic; WT, wild type. * Corresponding author. Tel.: +1-858-784-7259; fax: +1-858-784- 7393. E-mail address: tkrucker@scripps.edu (T. Krucker). www.elsevier.com/locate/jneuroim Journal of Neuroimmunology 150 (2004) 37 – 47