Age‐related deficits in neuronal physiology and cognitive function are recapitulated in young mice overexpressing the L‐type calcium channel, CaV1.3

The calcium dysregulation hypothesis of brain aging posits that an age‐related increase in neuronal calcium concentration is responsible for alterations in a variety of cellular processes that ultimately result in learning and memory deficits in aged individuals. We previously generated a novel transgenic mouse line, in which expression of the L‐type voltage‐gated calcium, CaV1.3, is increased by ~50% over wild‐type littermates. Here, we show that, in young mice, this increase is sufficient to drive changes in neuronal physiology and cognitive function similar to those observed in aged animals. Specifically, there is an increase in the magnitude of the postburst afterhyperpolarization, a deficit in spatial learning and memory (assessed by the Morris water maze), a deficit in recognition memory (assessed in novel object recognition), and an overgeneralization of fear to novel contexts (assessed by contextual fear conditioning). While overexpression of CaV1.3 recapitulated these key aspects of brain aging, it did not produce alterations in action potential firing rates, basal synaptic communication, or spine number/density. Taken together, these results suggest that increased expression of CaV1.3 in the aged brain is a crucial factor that acts in concert with age‐related changes in other processes to produce the full complement of structural, functional, and behavioral outcomes that are characteristic of aged animals. Here we revisit the hypothesis that dysregulation of calcium homeostasis in neurons underlies age‐related changes in neuronal function and cognition. To test this hypothesis, we examined the post burst afterhyperpolarization and spatial memory in young mice genetically engineered to overexpress the L‐VGCC CaV1.3 in glutamatergic neurons in the hippocampus and forebrain.