Syndecan-3-Deficient Mice Exhibit Enhanced LTP and Impaired Hippocampus-Dependent Memory Marko Kaksonen,* ,1 Ivan Pavlov,* ,†,1 Vootele Vo ˜ikar,* ,1 Sari E. Lauri,* ,†,2 Anni Hienola,* Ruusu Riekki,* ,† Merja Lakso,* ,3 Tomi Taira, † and Heikki Rauvala* ,4 *Laboratory of Molecular Neurobiology, Institute of Biotechnology and Department of Biosciences, P.O. Box 56, and † Division of Animal Physiology, Department of Biosciences, P.O. Box 65, University of Helsinki, 00014 Helsinki, Finland Syndecan-3 (N-syndecan) is a transmembrane heparan sulfate proteoglycan expressed predominantly in the ner- vous system in a developmentally regulated manner. Syn- decan-3 has been suggested to play a role in the devel- opment and plasticity of neuronal connections by linking extracellular signals to the regulation of the cytoskeleton. To study its physiological functions, we produced mice deficient in syndecan-3 by gene targeting. The mutant animals are healthy, are fertile, and have no apparent defects in the structure of the brain. We focused on char- acterizing the functions of the hippocampus, a brain area where expression of syndecan-3 is prominent in adults. Mice lacking syndecan-3 exhibited an enhanced level of long-term potentiation (LTP) in area CA1, while basal syn- aptic transmission and short-term plasticity were similar to those in wild-type animals. Further, the mutant mice were not responsive to the syndecan-3 ligand heparin- binding growth-associated molecule, which inhibits LTP in area CA1 in wild-type animals. Behavioral testing of the syndecan-3-deficient mice revealed impaired perfor- mance in tasks assessing hippocampal functioning. We suggest that syndecan-3 acts as an important modulator of synaptic plasticity that influences hippocampus-de- pendent memory. INTRODUCTION Heparan sulfate proteoglycans (HSPG) are abundant on most cell surfaces and are involved in a wide range of cell– cell and cell–matrix interactions. They are known to regulate cell adhesion, cell migration, differ- entiation, and growth factor signaling (for reviews, see Bernfield, 1999; Sanderson, 2001; Yamaguchi, 2001). In the nervous system, HSPGs are involved in neurogen- esis, neurite guidance, synaptogenesis, and synaptic plasticity (Yamaguchi, 2001). Syndecans together with glypicans form the two major families of cell-surface HSPGs (Bernfield et al., 1999). Syndecan-3 (N-syndecan) is one of the four mamma- lian syndecans and it is mainly expressed in the ner- vous system, especially during development (Carey et al., 1997). It has been suggested to function in cell ad- hesion, neurite guidance, and cell migration during development of the nervous system (Raulo et al., 1994). Syndecan-3 has also been implicated in the regulation of synaptic plasticity in the hippocampus (Lauri et al., 1999). Syndecan-3 is expressed in an activity-dependent manner in the CA1 pyramidal neurons, and application of exogenous syndecan inhibits the induction of long- term potentiation (LTP) (Lauri et al., 1999). Syndecan-3 has one transmembrane domain, a short cytoplasmic tail of 34 amino acids, and an extracellular domain that carries heparan sulfate chains (Carey et al., 1997). Syndecan-3 heparan sulfate chains bind to fibro- blast growth factor-2 (FGF-2) (Chernousov and Carey, 1993) and heparin-binding growth-associated molecule (HB-GAM) (Raulo et al., 1994). Syndecans have been suggested to function as coreceptors with other signal- ing receptors, such as FGF receptors and integrins 1 These authors contributed equally to this work. 2 Current address: Department of Anatomy, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK. 3 Current address: A. I. Virtanen Institute for Molecular Sciences, BioTeknia, Neulaniementie 2, 70210 Kuopio, Finland. 4 To whom correspondence should be addressed at the Laboratory of Molecular Neurobiology, Institute of Biotechnology and Depart- ment of Biosciences, P.O. Box 56 (Viikinkaari 5), FIN-00014 University of Helsinki, Finland. Fax: +358 9 191 59068. E-mail: heikki.rauvala@ helsinki.fi. doi:10.1006/mcne.2002.1167 Molecular and Cellular Neuroscience 21, 158–172 (2002) MCN 1044-7431/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved. 158