Affiliations: [a] SISSA (International School for Advanced Studies), via Beirut 2–4, 34014 Trieste, Italy | [b] Lay Line Genomics SpA, 00128 Roma, Italy | [c] 3Institute of Neuroscience, CNR, 56127 Pisa, Italy | [d] Department of Biomedical Sciences and Technologies, L'Aquila University, 67010 L'Aquila | [e] Fondazione Rita Levi Montalcini-European Brain Research Institute, 00143 Roma, Italy
Correspondence:
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Corresponding author: Prof.~Antonino Cattaneo, Fondazione Rita Levi-Montalcini- European Brain Research Institute, Via del Fosso di Fiorano 64, 00143 Roma, Italy. Tel.: +39 06 501703118; Fax: +39 06 50173302; E-mail: cattaneo@sissa.it.
Abstract: A deficit in cortical cholinergic synaptic transmission is a common feature of cognitive and behavioral impairment observed in neurodegenerative pathologies. AD11 transgenic mice producing blocking antibodies against Nerve Growth Factor (NGF) are characterized by a progressive neurodegenerative phenotype defined by the deposition of amyloid peptide, intracellular neurofibrillary tangles and by a marked cholinergic depletion. We exploited AD11 mice to develop a functional assay to investigate the impact of cholinergic deficit on cortical synaptic plasticity impairment at different neurodegenerative stages. In particular, we investigated the time course of long–term potentiation (LTP) impairment in neocortex of AD11 mice and potential rescue by acute pharmacological treatment with Acetylcholine (ACh) or the cholinergic agonist Galantamine (GAL). We showed that LTP starts being absent in AD11 mice at 2 months, an age corresponding to early neurodegenerative stage characterized by the first observed decrease in number of basal forebrain cholinergic neurons (BFCNs) without overt cortical neurodegeneration. We demonstrated that acute ACh or GAL treatment fully reverts LTP impairment in 2 month old AD11 mice. In contrast, cholinergic treatment failed to recover synaptic plasticity deficit in aged (9–10 months) AD11 mice characterized by a severe cortical neurodegeneration.
