Nimodipine and Learning in Aging Rabbits

Abstract

A major focus of our research has been to describe how neuronal excitability is changed during learning in the young adult brain and how neurons in the aging brain may be impaired in their ability to produce such changes. In our approach we have utilized eyeblink conditioning and the in vivo and in vitro rabbit hippocampus for behavioral, neurophysiological, and biophysical studies of associative learning. We have also investigated the potential contribution of nimodipine in enhancing learning in aging subjects, with a focus on the role of calcium-mediated processes in learning. The hippocampus is known to be important for learning and memory consolidation and to be profoundly affected by aging and Alzheimer’s disease. Hippocampal ablation was shown to block acquisition and/or extinction in eyeblink tasks, with effects most prominent in trace conditioning. Extracellular recordings in vivo have demonstrated increased excitability of hippocampal neurons to the conditioned stimulus in eyeblink conditioning. Experiments in our laboratory indicated that this increased excitability resulted from a conditioning-specific reduction in the post-burst afterhyperpolarization (AHP) of CA1 neurons in hippocampal slices. The AHP is a postsynaptic response regulating neuronal excitability and is generated by an outward calcium-dependent potassium current. This hyperpolarizing response is increased in aging hippocampal neurons, presumably as a result of increased intracellular calcium levels in aging neurons. Consequently, aging neurons are less able to increase their excitability and thus show adaptive change during associative learning. The calcium channel blocker nimodipine facilitated acquisition of trace eyeblink conditioning in the aging rabbit. Convergent data suggest that this learning enhancement may also be mediated by changes in hippocampal neuronal excitability. Nimodipine apparently increases excitability by reducing calcium influx through voltage-gated calcium channels, with a secondary reduction in the post-burst AHP. The relevance of our findings to potential clinical applications in aging and/or in Alzheimer’s disease is discussed.