Increased Neuronal Excitability, Synaptic Plasticity, and Learning in Aged Kvβ1.1 Knockout Mice

aged humans [3], rats [4], and mice [5] perform poorly in Background: Advancing age is typically accompanied tasks that require spatial learning strategies, suggesting by deficits in learning and memory. These deficits occur age-related impairments in hippocampal function. independently of overt pathology and are often considThe exact cause of these age-related deficits in hippoered to be a part of “normal aging.” At the neuronal level, campal-dependent learning and memory is not currently normal aging is known to be associated with numerous known. However, in recent years several promising cellular and molecular changes, which include a prohypotheses have emerged. Prominent among them is nounced decrease in neuronal excitability and an altered the calcium dysregulation hypothesis of brain aging and induction in the threshold for synaptic plasticity. Beneurodegeneration. This hypothesis asserts that a numcause both of these mechanisms (neuronal excitability ber of age-related changes in neuronal function, as well and synaptic plasticity) have been implicated as putative as neuronal dysfunction associated with Alzheimer’s cellular substrates for learning and memory, it is reasondisease (AD), may be the result of a dysregulation of able to propose that age-related changes in these mechthe homeostasis of cytosolic free calcium (for multiple anisms may contribute to the general cognitive decline reviews, see [6]). that occurs during aging. There is significant experimental evidence for an ageResults: To further investigate the relationship between related elevation in intracellular free calcium in pyramidal aging, learning and memory, neuronal excitability, and neurons in the hippocampus. The most direct evidence synaptic plasticity, we have carried out experiments with comes from calcium imaging studies that demonstrate aged mice that lack the auxiliary potassium channel a marked increase, in response to prolonged synaptic subunit Kv 1.1. In aged mice, the deletion of the auxiliary stimulation, in intracellular calcium levels in neurons potassium channel subunit Kv 1.1 resulted in increased from aged animals [7]. This age-related increase in intraneuronal excitability, as measured by a decrease in the cellular calcium is thought to have a number of functional post-burst afterhyperpolarization. In addition, long-term consequences. In the hippocampus, one of the betterpotentiation (LTP) was more readily induced in aged characterized changes secondary to the age-related inKv 1.1 knockout mice. Finally, the aged Kv 1.1 mutants crease in intracellular calcium is a decrease in postsynoutperformed age-matched controls in the hidden-plataptic neuronal excitability. This age-related decrease form version of the Morris water maze. Interestingly, in neuronal excitability is manifested by an increase in the enhancements in excitability and learning were both calcium-activated potassium currents. These currents sensitive to genetic background: The enhanced learning underlie the slow afterhyperpolarization (sAHP) that folwas only observed in a genetic background in which lows bursts of action potentials in hippocampal pyramithe mutants exhibited increased neuronal excitability. dal neurons. This age-related increase in the post-burst