TNF-a Receptor 1 Deficiency Enhances Kainic Acid–Induced Hippocampal Injury in Mice Ming-Ou Lu, 1 Xing-Mei Zhang, 1,2 Eilhard Mix, 3 Hernan Concha Quezada, 4 Tao Jin, 1,2 Jie Zhu, 1,2 * and Abdu Adem 5 1 Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden 2 Department of Neurology, the First Hospital, Jilin University, Changchun, China 3 Department of Neurology, University of Rostock, Rostock, Germany 4 Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden 5 Department of Pharmacology, Faculty of Medicine & Health Science, United Arab Emirates University, Al Ain, United Arab Emirates The exact role of TNF-a in excitotoxic neurodegenera- tion of the brain is unclear. To address this issue, the kainic acid (KA)–induced hippocampal injury model, a well-characterized model of human neurodegenerative diseases, was used in TNF-a receptor 1 (TNFR1)– knockout (TNFR1 2/2 ) mice in the present study. After nasal application of a single dose of 40 mg of KA per kilogram body weight, TNFR1 2/2 mice showed signifi- cantly more severe seizures than the wild-type mice. In addition, obvious neurodegeneration, enhanced micro- glia activation, and astrogliosis in the hippocampus, as well as increased locomotor activity, were found in TNFR1 2/2 mice compared with the wild-type controls 8 days after KA delivery. Moreover, CC chemokine recep- tor 3 expression on activated microglia was increased 3 days after KA treatment in TNFR1 2/2 mice, as meas- ured by flow cytometry. These data suggest that TNF-a may play a protective role through TNFR1 signal- ing. V V C 2008 Wiley-Liss, Inc. Key words: kainic acid; neurodegeneration; TNF-a; TNF-a receptor 1 deficiency; hippocampus Neuronal excitation involving the excitatory gluta- mate receptors is recognized as an important mechanism underlying neurodegeneration (Wang et al., 2005). In mice, the administration of kainic acid (KA), an ana- logue of the excitotoxin glutamate, results in hippocam- pal cell death and seizures, providing a well-characterized model for studies of human neurodegenerative diseases (Chen et al., 2002). In the course of KA-induced hippo- campal injury, neurons interact with the surrounding cells, including astrocytes and microglia. Modulation of the activity of these cells, for example, via cytokines, may influence the survival and repair of hippocampal neurons after injury (Chen et al., 2004). The proinflammatory cytokine tumor necrosis fac- tor-a (TNF-a) is a 17-kDa protein mainly produced by activated macrophages and T cells in the immune system and by microglia and astrocytes in the nervous system. Initially characterized as having antitumor activity, it was later found to exert pleiotropic, often contradictory bio- logical activities (Previtali et al., 1997; Cope, 1998; Bachmann et al., 1999; Eugster et al., 1999; Kassiotis et al., 2001; Bao et al., 2003; Zhu et al., 2003). Its func- tions are mediated through two receptors, TNFR1 (p55) and TNFR2 (p75), both of which are expressed on vari- ous cells types (Ware et al., 1991). The majority of bio- logical responses classically attributed to TNF-a are mediated by TNFR1 (Bachmann et al., 1999; Bao et al., 2003). TNF-a overexpression is implicated in the patho- genesis of several human central nervous system (CNS) disorders, notably bacterial meningitis (Leist et al., 1988), multiple sclerosis (Raine, 1995), and cerebral malaria (Grau et al., 1989), where inflammatory cells contribute significantly to locally elevated TNF-a levels. Also, Alz- heimer’s disease is accompanied by rapid up-regulation of TNF-a (Zhao et al., 2003). Moreover, TNF-a potentiates excitotoxic injury to human fetal brain cell cultures (Chao and Hu, 1994). However, an increasing amount of evidence suggests that partial or absent TNF- a functioning is also potentially detrimental to the integ- rity of the CNS. For example, knockout of TNF-a worsened Listeria infection (Rothe et al., 1993), and in mice lacking TNF-a receptors, neuronal damage was enhanced after excitotoxic (Bruce et al., 1996), ischemic (Bruce et al., 1996), or traumatic (Sullivan et al., 1999) Contract grant sponsor: Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences; Contract grant number: MRG 16, 2005–2206. *Correspondence to: Dr. Jie Zhu, Division of Neurodegeneration and Neuroinflammation (NOVUM, plan 5), Karolinska Institute, Karolinska University Hospital in Huddinge, SE-141 86 Stockholm, Sweden. E-mail: jie.zhu@ki.se Received 2 May 2007; Revised 20 September and 17 October 2007; Accepted 20 October 2007 Published online 11 January 2008 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/jnr.21600 Journal of Neuroscience Research 86:1608–1614 (2008) ' 2008 Wiley-Liss, Inc.