Hippocampal P3-Like Auditory Event-Related Potentials are Disrupted in a Rat Model of Cholinergic Degeneration in Alzheimer's Disease: Reversal by Donepezil Treatment

Article type: Research Article

Authors: Laursen, Bettina^{a; b; *} | Mørk, Arne^a | Kristiansen, Uffe^b | Bastlund, Jesper Frank^a

Affiliations: [a] H. Lundbeck A/S, Synaptic Transmission 1, Valby, Denmark | [b] Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark

Correspondence: [*] Correspondence to: Bettina Laursen, PhD, H. Lundbeck A/S, Synaptic Transmission 1, Ottiliavej 9, 2500 Valby, Denmark. Tel.: +45 35 33 60 00; Fax: +45 35 33 60 01; E-mail: xbc@lundbeck.com.

Abstract: P300 (P3) event-related potentials (ERPs) have been suggested to be an endogenous marker of cognitive function and auditory oddball paradigms are frequently used to evaluate P3 ERPs in clinical settings. Deficits in P3 amplitude and latency reflect some of the neurological dysfunctions related to several psychiatric and neurological diseases, e.g., Alzheimer's disease (AD). However, only a very limited number of rodent studies have addressed the back-translational validity of the P3-like ERPs as suitable markers of cognition. Thus, the potential of rodent P3-like ERPs to predict pro-cognitive effects in humans remains to be fully validated. The current study characterizes P3-like ERPs in the 192-IgG-SAP (SAP) rat model of the cholinergic degeneration associated with AD. Following training in a combined auditory oddball and lever-press setup, rats were subjected to bilateral intracerebroventricular infusion of 1.25 μg SAP or PBS (sham lesion) and recording electrodes were implanted in hippocampal CA1. Relative to sham-lesioned rats, SAP-lesioned rats had significantly reduced amplitude of P3-like ERPs. P3 amplitude was significantly increased in SAP-treated rats following pre-treatment with 1 mg/kg donepezil. Infusion of SAP reduced the hippocampal choline acetyltransferase activity by 75%. Behaviorally defined cognitive performance was comparable between treatment groups. The present study suggests that AD-like deficits in P3-like ERPs may be mimicked by the basal forebrain cholinergic degeneration induced by SAP. SAP-lesioned rats may constitute a suitable model to test the efficacy of pro-cognitive substances in an applied experimental setup.

Keywords: Alzheimer's disease, donepezil, 192-IgG-SAP, P300 event-related potential, rat

DOI: 10.3233/JAD-131502

Journal: Journal of Alzheimer's Disease, vol. 42, no. 4, pp. 1179-1189, 2014