P3‐373: Effects of chronic and acute simvastatin on neuronal excitability and LTP in APPswe/PS1dE9 mice
Caroline E. Herron, Charles Métais · Alzheimer s & Dementia · 2010
Recent studies have investigated the potential therapeutic properties of statins; agents commonly used to treat hypercholesterolemia. Behavioural studies in Tg2576 mice, demonstrated that chronic treatment with simvastatin improved learning and memory (Li et al., 2006; Ann Neurol 60: 729-739). In cultured neurones, chronic mevastatin treatment however depressed NMDA receptor-mediated current yet enhanced voltage-gated sodium channel current (Kannan et al., Neurobiology of Aging 2008). Here we have investigated the effects of acute and chronic simvastatin treatment on synaptic transmission, action potential regulation and synaptic plasticity in the APPswe/PS1dE9 mouse model. Mice were treated chronically by including simvastatin in their diet (0.04%) for periods of 3 to 6 months. Alternatively simvastatin was applied via the perfusion solution. Electrophysiological recordings were performed in transverse hippocampal slices from APPswe/PS1dE9 mice and age matched controls. Antidromic compound action potentials (cAPs) were recorded in the CA1 cell body region by stimulating the alveus (in DNQX). Excitatory post synaptic potentials (EPSPs) were evoked in the CA1 region every 30s and paired pulse facilitation (PPF) examined to assess neurotransmitter release. Stable baseline responses were recorded prior to application of simvastatin or LTP induction. LTP was induced using two trains of stimuli at 100Hz for one second applied 30s apart. In control mice (18month), acute application of simvastatin (35μM) caused a significant increase in the amplitude of the cAP, a shift in the input/put put curve and a decrease in PPF while in age matched APPswe/PS1dE9 mice acute simvastatin had no affect. A lower concentration (10μM) also caused an increased in cAP amplitude which was absent in slices from APPswe/PS1dE9 mice.This increased excitability is blocked by antagonists of PI3 kinase. Acute simvastatin application also had no effect in slices from animals previously treated chronically with simvastatin in their diet. In addition, chronic simvastatin treatment rescued LTP in APPSwe/PS1dE9 mice (18 and 8 months old) however it failed to rescue STP. Chronic simvastatin treatment can therefore rescue LTP in hippocampal CA1 in APPswe/PS1dE9 mice. In addition, acute simvastatin enhances neuronal excitability via a PI3 kinase dependent mechanism which is absent in slices from APPswe/PS1dE9 mice.