# Molecular mechanisms of memory maintenance and dysfunction in neural circuits

> **NIH NIH R01** · SUNY DOWNSTATE MEDICAL CENTER · 2020 · $717,788

## Abstract

How molecular mechanisms modify neuronal networks to maintain long-term memory is a fundamental
question in neuroscience, with relevance for disorders of persistent, memory-like dysfunction of brain circuits.
Atypical PKCs (aPKC), the persistently active isoform PKMζ and PKCι/λ, are core molecules maintaining late-
phase synaptic long-term potentiation (LTP) and several forms of long-term memory. Unlike most PKCs that
are active only briefly after stimulation, aPKCs have persistent actions. After strong synaptic stimulation, PKMζ
increases by new synthesis, and the persistent increase in the autonomously active isoform enhances synaptic
transmission during LTP maintenance and lasts for days to weeks during long-term memory storage. The other
aPKC, PKCι/λ, can also maintain LTP and long-term memory, as revealed by PKMζ-knockout (KO) mice.
Inhibitors of aPKC disrupt memory even weeks after it is formed and ameliorate persistent symptoms of PTSD,
addiction, and chronic neuropathic pain in specific brain circuits in animal models. Conversely, overexpressing
PKMζ enhances long-term memory and alleviates persistent deficits in disorders in which decreased PKMζ is
implicated. Thus, understanding how aPKCs contribute to maintaining memory by sustaining representations
of memory in brain circuits will provide fundamental information to assess their roles in pathological memory.
 Therefore, our Specific Aims are: Aim 1: Is there a hierarchy of PKCs in memory maintenance that
store representations differently in networks of neurons? Spatial memory representations depend on the
discharge of hippocampus place cell ensembles. We will examine if the properties of hippocampus place cell
ensemble representations of spatial memories differ when maintained by PKMζ or PKCι/λ, and if other PKCs
can also maintain spatial memory. Aim 2: How are spatial memory-related place cell ensemble
representations modified when memory is erased by inhibiting individual PKCs in wild-type and PKMζ-
KO mice? Using novel isoform-selective antagonists and conditional KO (cKO) mice, we will test the necessity
of aPKC-mediated enhanced synaptic connectivity for representing spatial memory by examining whether
reversing this connectivity concurrently erases memory and destabilizes memory-related place cell ensemble
representations. Aim 3: Does persistently increased synthesis of PKMζ maintain very long-term
memory? Strong conditioning produces increases in PKMζ in the hippocampus that last a month. We will use
PKMζ-antisense and PKMζ-cKOs to determine if these persistent increases are due to persistent increased
synthesis and/or decreased degradation. To test sufficiency of PKMζ for maintaining memory and memory-
related representations of space, we will use overexpression of PKMζ that prolongs long-term memory to
examine if increased PKMζ synthesis also perpetuates memory-related place cell ensemble representations.
Our aims will elucidate the persistent molecular mechanisms maintaining ...

## Key facts

- **NIH application ID:** 9884816
- **Project number:** 5R01MH115304-03
- **Recipient organization:** SUNY DOWNSTATE MEDICAL CENTER
- **Principal Investigator:** ANDRE ANTONIO FENTON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $717,788
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9884816

## Citation

> US National Institutes of Health, RePORTER application 9884816, Molecular mechanisms of memory maintenance and dysfunction in neural circuits (5R01MH115304-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9884816. Licensed CC0.

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