# PROJECT 4-NPTX2 and Adaptation to Cognitive Aging

> **NIH NIH P01** · JOHNS HOPKINS UNIVERSITY · 2021 · $485,315

## Abstract

Project 4 examines the role of NPTX2 and homeostatic scaling in age-related cognitive decline. NPTX2 is an
immediate early gene expressed by pyramidal neurons and mediates activity-dependent homeostatic
strengthening of inhibitory circuits by adaptively strengthening excitatory drive of parvalbumin interneurons
(PV-IN). This PPG has examined the effect of aging on cognition using outbred Long-Evans rats and has
documented increased pyramidal neuron excitability and reduced PV-IN circuit inhibition that are associated
with cognitive decline. Preliminary studies further reveal reduced NPTX2 expression in Aged-Impaired rats and
rescue of circuit deficits by NPTX2 transgene expression. Here, we build on these observations and examine
the hypothesis that failure of NPTX2 homeostatic mechanisms contribute to age-related cognitive decline. Aim
1 will test the hypotheses that NPTX2 loss-of-function (LOF) accelerates age-related cognitive decline while
NPTX2 gain-of-function (GOF) delays or prevents age-related cognitive decline. A conditional NPTX2 LOF
model uses a newly developed NPTX2f/f rat together with virus-mediated delivery of Cre to delete NPTX2 at 11
m and together with Core B details the impact on cognitive behavior. In a reciprocal set of experiments, we
create NPTX2 GOF models using two distinct approaches that include virus mediated NPTX2 transgene and
oligonucleotide mediated NPTX2 mRNA stabilization. The impact of GOF on cognitive behavior is evaluated in
collaboration with Core B. Aim 2 examines molecular and cellular mechanisms mediating dynamic targeting of
NPTX2 to excitatory synapses. Studies use state-of-the-art proximity labeling methods to identify proteins
involved in synaptic NPTX2 exocytosis and shedding. Aim 3 uses in vivo 2-photon imaging to examine the
hypothesis that age-related cognitive deficits are associated with disruption of a critical phase of homeostatic
scaling that mediates activity-dependent NPTX2 exocytosis and shedding. Analyses examine diurnal changes
in synaptic NPTX2 in association with waking behaviors and sleep comparing Young, Aged-Impaired and
Aged-Unimpaired rats. We also test the effect of levetiracetam in Aged-Impaired rats. Studies in Aims 1 and 3
include both male and female rats. The Aims are highly synergistic with other Projects and together will reveal
fundamental mechanisms of aging, cognitive resilience and cognitive decline.

## Key facts

- **NIH application ID:** 10171063
- **Project number:** 2P01AG009973-26A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** PAUL F WORLEY
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $485,315
- **Award type:** 2
- **Project period:** 1997-09-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171063

## Citation

> US National Institutes of Health, RePORTER application 10171063, PROJECT 4-NPTX2 and Adaptation to Cognitive Aging (2P01AG009973-26A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10171063. Licensed CC0.

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