# Slow Outward Currents and Learning In Aging Hippocampus

> **NIH NIH R37** · NORTHWESTERN UNIVERSITY · 2020 · $366,899

## Abstract

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
CAI 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 CAI 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 CAI neurons is elevated in aged rats,
which provides a molecular mechanism for the reported increased Ca2+ influx through LTCC in aged CAI
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 determined from protein microarray experiments (a new powerful method to screen
expression level changes in hundreds of proteins), and confirmed through literature review and further
molecular (e.g., western blot) assays. In addition, we will identify the source(s) ofthe elevated Ca2+
accumulation in aged CAI neurons using Ca2+ imaging with two-photon laser scanning microscopy; and
thus, reveal additional potential therapeutic targets for intervention. Our goals remain unchanged: to confirm
that the AHP is the key regulator of intrinsic excitability and that targeted molecular methods to reduce the
AHP in CAI neurons in aged subjects will lead to successful learning. Continued success will indicate that
the protein being manipulated is a viable candidate to target as a therapeutic intervention point for age-
associated learning impairments. This research program has clear relevance to understanding and treating
neurodegenerative diseases such as Alzheimer's Disease, in which aging is the pr...

## Key facts

- **NIH application ID:** 10205720
- **Project number:** 3R37AG008796-28S1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** JOHN F DISTERHOFT
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,899
- **Award type:** 3
- **Project period:** 1990-03-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10205720

## Citation

> US National Institutes of Health, RePORTER application 10205720, Slow Outward Currents and Learning In Aging Hippocampus (3R37AG008796-28S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10205720. Licensed CC0.

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