Disrupted cross-laminar cortical processing in β amyloid pathology precedes cell death H. Lison a , M.F.K. Happel a , F. Schneider b , K. Baldauf b , S. Kerbstat b , B. Seelbinder a , J. Schneeberg b , M. Zappe b , J. Goldschmidt a , E. Budinger a , U.H. Schröder a , F.W. Ohl a , S. Schilling c , H.-U. Demuth c , H. Scheich a , K.G. Reymann a,b , R. Rönicke b,d, ⁎ a Leibniz-Institute for Neurobiology, Brenneckestr. 6, 39118 Magdeburg, Germany b Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), c/o Universitätsklinikum Magdeburg, Leipziger Strasse 44/Haus 64, 39120 Magdeburg, Germany c Probiodrug AG, Weinbergweg 22, 06120 Halle (Saale), Germany d Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany abstract article info Article history: Received 4 July 2013 Revised 4 October 2013 Accepted 19 November 2013 Available online 27 November 2013 Keywords: β amyloid Cortical column Glutaminyl cyclase Network disruption Thallium uptake Disruption of neuronal networks in the Alzheimer-afflicted brain is increasingly recognized as a key correlate of cognitive and memory decline in Alzheimer patients. We hypothesized that functional synaptic disconnections within cortical columnar microcircuits by pathological β-amyloid accumulation, rather than cell death, initially causes the cognitive impairments. During development of cortical β-amyloidosis with still few plaques in the transgenic 5xFAD mouse model single cell resolution mapping of neuronal thallium uptake revealed that electrical activity of pyramidal cells breaks down throughout infragranular cortical layer V long before cell death occurs. Treatment of 5xFAD mice with the glutaminyl cyclase inhibitor, PQ 529, partially prevented the decline of pyramidal cell activity, indicating pyroglutamate-modified forms, potentially mixed oligomers of Aβ are contributing to neuronal impairment. Laminar investigation of cortical circuit dysfunction with current source density analysis identified an early loss of excitatory synaptic input in infragranular layers, linked to pathological recurrent activations in supragranular layers. This specific disruption of normal cross-laminar cortical processing coincided with a decline of contextual fear learning. © 2013 Elsevier Inc. All rights reserved. Introduction Progressive impairment of cognitive domains as declarative memory, language and semantic interpretation of percepts is a characteristic symptomatic feature of Alzheimer's disease (AD) (Cummings and Cole, 2002). These symptoms are likely due to cortical and limbic malfunctions which largely correlate with AD-related pathological alterations within the respective regions (Thal et al., 2002). While β-amyloid plaques and neurofibrillary tangles are accepted as the pathological hallmarks of AD, it is still unclear how this pathology causes impairment of cognition. Progressive neuronal loss as described for particular regions of the AD brain in humans (West et al., 1994) and in AD animal models (Wirths and Bayer, 2010) is usually taken respon- sible for the mental derangement at late stages of the disease. However, theoretical considerations and recent investigations support the view that during early phases of AD dysfunction of neuronal networks within and between the cortex and limbic systems are of greater significance for cognitive impairment. Computational neurosci- ence studies demonstrate that disseminated cell death per se cannot induce the specific pattern of gradual amnesia that occurs in AD (Small et al., 2001). Furthermore, pronounced fluctuation of mental capabilities observed in AD patients can be plausibly explained with labile neuronal Alzheimer's functions (Palop et al., 2006). Extensive data indicate a central pathogenic role for β-amyloid in Alzheimer's disease (Hardy and Selkoe, 2002), suggesting its pivotal contribution to AD-related neuronal network disruption. Indeed, fMRI studies in patients with mild cognitive impairment indicate abnormal function of neuronal networks, correlating with β-amyloid accumulation (Drzezga et al., 2011; Sperling et al., 2009). Supporting these findings in human patients, investigations of AD mouse models, transgenic for the human β-amyloid precursor protein (hAPP), revealed dysregulation of neuronal activity in the hippocampal network (Palop et al., 2007) and small cortical circuits (Busche et al., 2008). Since these transgenic mouse models recapitulate a variety of AD-like abnormalities (Games et al., 1995; Lesné et al., 2006), they can provide mechanistic insights of high relevance to the human condition. Neurobiology of Disease 63 (2014) 62–73 Abbreviations: (APP), β-amyloid precursor protein; (AD), Alzheimer's disease; (Tl-AMG), thallium autometallography; (TlDDC), thallium diethyl-dithiocarbamate; (QC), glutaminyl cyclase; (CSD), current source density; (LFP), local field potential; (ICMS), intracortical microstimulation; (FFT), Fast Fourier Transformation. ⁎ Corresponding author at: Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany. E-mail address: raik.roenicke@med.ovgu.de (R. Rönicke). Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.nbd.2013.11.014 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi