Journal
AGING CELL
Volume 22, Issue 3, Pages -Publisher
WILEY
DOI: 10.1111/acel.13781
Keywords
afterhyperpolarization; fear generalization; learning and memory; mouse; novel object recognition
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The calcium dysregulation hypothesis suggests that increased neuronal calcium concentration in the aging brain is responsible for learning and memory deficits. Researchers generated transgenic mice with increased expression of the L-type voltage-gated calcium channel, Ca(V)1.3, and found that this increase led to changes in neuronal physiology and cognitive function similar to those seen in aged animals.
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, Ca(V)1.3, is increased by similar to 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 Ca(V)1.3 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 Ca(V)1.3 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.
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