# Towards a critical test of the synaptic plasticity and memory hypothesis

> **NIH NIH R01** · NEW YORK UNIVERSITY · 2024 · $578,712

## Abstract

How memory is stored in the brain is unknown. The dominant synaptic plasticity and memory (SPM)
hypothesis asserts that memory is stored by functional modifications induced by learning at a subset of the
synapses of the neurons that are activated to encode the learning experience. This predicts permanent
memory erasure is caused by post-learning inhibition of a molecular synaptic plasticity maintenence
mechanism that is necessary for persistent storage of the long-term memory. Indeed, erasure of a variety of
memories has been demonstrated by intracranial ZIP administration. ZIP inhibits the kinase activity of atypical
PKCs, PKMζ and PKCι/λ, both of which can be persistently upregulated following memory acquisition. PKMζ
is both necessary and sufficient for wildtype late-LTP maintenance, and when the PKMζ gene Prkcz is deleted,
PKCι/λ compensates for the loss of PKMζ, becoming necessary for maintaining late-LTP. Intracranial aPKC
manipulations erase a variety of long-term memories, but not all, providing crucial support for the foundational
SPM hypothesis. However, because the manipulations act generally, affecting cells that may not participate in
the memory storage, it is crucial to selectively depotentiate synapses in a memory-associated subset of cells to
critically test the SPM hypothesis. Indeed, others have used the fact that memory formation requires protein
synthesis to challenge the SPM hypothesis. They demonstrated that post-learning optogenetic stimulation of a
context-fear memory-activated subset of hippocampal neurons is sufficient to express the memory, even after
an amnesia-producing block of protein synthesis. However, these studies did not critically test the SPM
hypothesis because neither hippocampus function, nor the most common N-Methyl-D-Aspartate receptor
(NMDAR)- and aPKC-dependent form of LTP in the hippocampus are necessary for context-fear memory,
amongst other experimental issues. We propose to critically test the SPM hypothesis using 1) a long-term
active place avoidance memory that is sufficient to induce persistent hippocampal synaptic potentiation, and
depends on hippocampus PKMζ, both for at least 30 days; 2) optogenetic activation of neurons that is
sufficient to express the avoidance memory; and 3) aPKC manipulations that are genetically targeted to the
memory-associated subset of cells. We will optogenetically activate a “sufficient-for-memory” subset of the
hippocampal neurons that are allocated to encode and recall a specific place memory, after erasing the
memory and associated synaptic plasticity by aPKC manipulation of the same cells. We will evaluate if after
erasure, optogenetic activation of the memory-associated cells expresses the spatial information in neural
discharge and the conditioned avoidance behavior that express the memory. If the optogenetic activation
causes memory expression, the SPM hypothesis will require modification, at least as far as it it concerns
aPKC-dependent synaptic plasticity a...

## Key facts

- **NIH application ID:** 10817077
- **Project number:** 5R01MH132204-02
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** ANDRE ANTONIO FENTON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $578,712
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817077

## Citation

> US National Institutes of Health, RePORTER application 10817077, Towards a critical test of the synaptic plasticity and memory hypothesis (5R01MH132204-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10817077. Licensed CC0.

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