# De novo Synthesis and Memory

> **NIH NIH R35** · JOHNS HOPKINS UNIVERSITY · 2021 · $573,125

## Abstract

Project Summary
Memory is our most precious possession, yet we remain unable to prevent its loss in neurological diseases.
Here we examine a fundamental property of memory, which is its dependence on rapid de novo protein
synthesis, and identify pathways that contribute to normal memory and that underlie human memory loss. Dr.
Worley's laboratory pioneered the discovery and analysis of cellular immediate early genes (IEGs) as effectors
of protein synthesis-dependent memory, and has described mechanisms mediated by IEGs Arc, Homer 1a and
NPTX2 at excitatory synapses that strengthen active synapses and weaken inactive synapses. Emerging
concepts integrate their individual molecular and synaptic functions into a temporal program of sequential
cellular and circuit adaptations that encode information. The process begins with Arc and Homer1a, which act
cell-autonomously to control the synaptic expression of AMPA type glutamate receptors. A later process
mediated by secreted NPTX2 acts non cell-autonomously to strengthen excitatory synapses on a specific class
of inhibitory neurons that express parvalbumin. Studies from mouse models indicate that down regulation of
NPTX2 results in increased neural activity that may occlude the ability of networks to encode information, as
well as a propensity for activity-dependent pathology including seizures and Aß amyloid generation.
Remarkably, aspects of this inhibitory network phase of information storage can be monitored in living human
subjects. Secreted NPTX2 is detected in human CSF and is prominently down-regulated in neurological
diseases in association with cognitive deterioration. We hypothesize that NPTX2 down-regulation provides a
rational biomarker of cognitive status in human neurological disease and may be is causal for certain memory
deficits. Basic studies will examine the unusual regulatory mechanisms that control NPTX2 expression and
function, and identify processes that result in its down-regulation in human brain. We will also gain deeper
insight into how IEGs, and NPTX2 in particular, contribute to memory using gain and loss of function
approaches in in vivo models of activity-dependent network plasticity including hippocampal replay. Stable,
long-term support will allow us to establish a multidisciplinary research program that leverages the strengths of
the Neuroscience community at Johns Hopkins for basic studies, and the Clinical Departments of
Neuropathology and Psychiatry at Johns Hopkins and Neurology at UC San Diego for translational aspects of
disease research. These studies will establish a novel, rational, and translatable concept for why humans lose
memory function in disease.

## Key facts

- **NIH application ID:** 10056993
- **Project number:** 5R35NS097966-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** PAUL F WORLEY
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $573,125
- **Award type:** 5
- **Project period:** 2016-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10056993

## Citation

> US National Institutes of Health, RePORTER application 10056993, De novo Synthesis and Memory (5R35NS097966-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10056993. Licensed CC0.

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