Age-related alterations of neuronal excitability and voltage-dependent Ca2+ current in a spontaneous mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common age-dependent neurodegenerative disorder, characterized by a progressive dysfunction of central neurons, and senescence-accelerated mouse prone 8 (SAMP8), a spontaneous AD mouse model, appears to be an excellent model to investigate the process of AD. Previous studies have indicated that neuronal excitability is impaired in transgenic AD mice. In this study, the cognition of SAMP8 mice was tested using the passive avoidance task and Morris water maze; whole-cell current-clamp recordings were used to evaluate the neuronal excitability, including the resting membrane potential, the number of action potentials, and after-hyperpolarization; and the voltage-dependent Ca2+ current in hippocampal slices was measured using whole-cell voltage-clamp recordings. We found that compared to the young mice, the performance in the learning and memory behavior tasks was impaired in aged mice, and the hippocampal CA1 pyramidal neurons of the aged mice showed a significantly depolarized resting membrane potential, increased numbers of action potentials after injection of depolarizing current, and increased after-hyperpolarization after the action potentials. Consistent with the above changes, the voltage-dependent Ca2+ current was larger in aged mice than in young mice. These data suggested that the aged SAMP8 neurons were hyperexcitable, and the alterations in the voltage-dependent Ca2+ current of aged neurons occurred in parallel to the elevation in excitability.