Slow Outward Currents and Learning In Aging Hippocampus

The hippocampus is critically involved in the early stages of declarative learning, and its function and capacity are degraded during normal aging that causes age-associated learning impairments. It has been repeatedly demonstrated that a cellular biomarker of this age-associated learning deficit is the enlarged Ca2+-dependent postburst afterhyperpolarization (AHP) that reduces the intrinsic excitability of CA1 pyramidal neurons in aged subjects. Thus, we have hypothesized that restoring intrinsic excitability of aged CA1 neurons to a young-like state by reducing the AHP using genetic manipulations would rescue the age-related learning deficits. Hence we have designed a research program to identify the candidate proteins for genetic manipulation with the use of recombinant adeno-associated viral (AAV) vectors. In the initial 3.5 years of this MERIT award, we have determined that 1) Ca2+ accumulation in the cytosol evoked with trains of action potentials is greatly elevated in aged CA1 neurons and may underlie the enlarged AHP in these neurons; 2) Ca2+ buffer capacity is increased in aged CA1 neurons, potentially as a cellular mechanism to counteract the increased Ca2+ accumulation; 3) CREB activation (an important cellular mechanism for protein synthesis necessary for learning and for AHP reduction) is impaired in hippocampus of aged rats; and 4) L-type Ca2+ channel (LTCC) expression on the surface of CA1 neurons is elevated in aged rats, which provides a molecular mechanism for the reported increased Ca2+ influx through LTCC in aged CA1 neurons. Based on these findings, we have identified Ca2+ binding proteins, CREB, and LTCC as candidates to rescue the age-related deficits by manipulating their function with AAV vectors. We have created AAV vectors targeting CREB and LTCC, and will continue the systematic characterization of their potential as therapeutics for restoring the age-related deficits. The candidate Ca2+ binding protein genes to manipulate will be determ