Synaptic dysfunction in hippocampus of transgenic mouse models of Alzheimer's disease: A multi-electrode array study Seon-Ah Chong a, b , Iryna Benilova f, g , Hamdy Shaban e , Bart De Strooper f, g , Herman Devijver d , Dieder Moechars e , Wolfgang Eberle a , Carmen Bartic a, c , Fred Van Leuven d, ⁎, Geert Callewaert b, ⁎⁎ a Bio-Electronic Systems, Imec, Kapeldreef 75, Leuven, Belgium b Research Group Neurodegeneration, KULeuven, Kortrijk, Belgium c Laboratory of Solid State Physics and Magnetism, Department of Physics and Astronomy, KULeuven, Leuven, Belgium d Experimental Genetics Group - LEGTEGG, KULeuven, Leuven, Belgium e CNS discovery, Janssen, Turnhoutseweg 30, Beerse, Belgium f Department for Molecular and Developmental Genetics, Flanders Institute for Biotechnology (VIB), Leuven, Belgium g Laboratory for the Research of Neurodegenerative diseases, Center for Human Genetics, KULeuven, Leuven, Belgium abstract article info Article history: Received 15 February 2011 Revised 19 May 2011 Accepted 6 July 2011 Available online 18 July 2011 Keywords: AD transgenic mice Amyloid Tau Synaptic dysfunction Hippocampal slices Multi-electrode arrays Dual recordings APP.V717I and Tau.P301L transgenic mice develop Alzheimer's disease pathology comprising important aspects of human disease including increased levels of amyloid peptides, cognitive and motor impairment, amyloid plaques and neurofibrillary tangles. The combined model, APP.V717I × Tau.P301L bigenic mice (biAT mice) exhibit aggravated amyloid and tau pathology with severe cognitive and behavioral defects. In the present study, we investigated early changes in synaptic function in the CA1 and CA3 regions of acute hippocampal slices of young APP.V717I, Tau.P301L and biAT transgenic animals. We have used planar multi- electrode arrays (MEA) and improved methods for simultaneous multi-site recordings from two hippocampal sub-regions. In the CA1 region, long-term potentiation (LTP) was severely impaired in all transgenic animals when compared with age-matched wild-type controls, while basal synaptic transmission and paired-pulse facilitation were minimally affected. In the CA3 region, LTP was normal in Tau.P301L and APP.V717I but clearly impaired in biAT mice. Surprisingly, frequency facilitation in CA3 was significantly enhanced in Tau. P301L mice, while not affected in APP.V717I mice and depressed in biAT mice. The findings demonstrate important synaptic changes that differ considerably in the hippocampal sub-regions already at young age, well before the typical amyloid or tau pathology is evident. © 2011 Elsevier Inc. All rights reserved. Introduction Transgenic mouse models overexpressing human mutant amyloid precursor protein (APP) or microtubule associated protein tau show various pathological hallmarks of Alzheimer's disease (AD) (Denk and Wade-Martins, 2009; Goetz and Ittner, 2008; Jaworski et al., 2010). Bigenic or triple transgenic mice have also been developed to study the complexity of AD by the combined amyloid and tau pathology (Lewis et al., 2001; Oddo et al., 2003). Here, we investigated early synaptic changes of young adult (4–6 months) tau and APP transgenic mice, separately and combined in a bigenic model that recapitulates amyloid and tau pathology synergistically (Terwel et al., 2008). APP. V717I transgenic mice progressively develop increased levels of APP intermediates and soluble amyloid peptides (Aβ) by 3 months of age, causing early cognitive impairment before clear deposition of extracellular plaques after 12 months (Moechars et al., 1999). Similarly, age-dependent tau hyperphosphorylation is developed in Tau.P301L transgenic mice by 3 months of age, leading to neurofi- brillary tangles (NFT) and motor deficits at older age (Boekhoorn et al., 2006; Dutschmann et al., 2010; Terwel et al., 2005). APP. V717I × Tau.P301L bigenic (biAT) mice develop combined amyloid plaques and NFT from 10 months, however amyloid accumulation is already observed at young age (3 months) (Terwel et al., 2008). Tau and APP transgenic models show altered synaptic transmis- sion and plasticity in the hippocampus (Fitzjohn et al., 2001; Rosenmann et al., 2008). Synaptic alterations have been observed at young age, well before amyloid deposits or tau aggregates are evident. Different APP transgenic strains exhibit LTP deficits at 2–6 months of age either associated or not with changes in pre- and basal synaptic transmission in the CA1 region (Giacchino et al., 2000; Hsia et al., 1999; Larson et al., 1999; Moechars et al., 1999; Saganich et al., 2006). Synaptic dysfunctions in young tau transgenic models have not been studied extensively. A double tau mutant model did not show deficit in basal synaptic transmission in CA1 at 6 months of age (Schindowski Neurobiology of Disease 44 (2011) 284–291 ⁎ Corresponding author. Fax: +32 16 345 871. ⁎⁎ Corresponding author. Fax: + 32 56 246 994. E-mail addresses: fred.vanleuven@med.kuleuven.be (F. Van Leuven), Geert.Callewaert@kuleuven-kortrijk.be (G. Callewaert). Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2011.07.006 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi