# Regulation and Neural Function of Atypical PKC

> **NIH NIH R37** · SUNY DOWNSTATE MEDICAL CENTER · 2020 · $403,750

## Abstract

Long-term memories are believed to be due to persistent changes in synaptic strength. Although the
molecular mechanisms initiating these changes have been extensively studied, the mechanisms
maintaining these changes, which may contribute to storing long-term memory, have been unknown.
Recently, however, a candidate molecular mechanism has emerged for maintaining a persistent form of
synaptic enhancement triggered by strong afferent stimulation of synapses, known as long-term
potentiation (LTP). The key molecule in this maintenance mechanism is a brain-specific, protein kinase
C isoform, PKMζ. Unlike other PKC isoforms that require second messengers for activation, PKMζ
consists of an independent PKC catalytic domain that is constitutively active. PKMζ is produced from a
PKMζ mRNA, and the amount of the kinase increases with LTP induction. The persistent activity of the
kinase is then both necessary and sufficient for maintaining the synaptic enhancement. Postsynaptic
perfusion of PKMζ enhances synaptic transmission, and inhibition of PKMζ activity reverses previously
established LTP. Recently, PKMζ inhibition has been found to disrupt the storage of previously
established long-term memories. These data indicate that PKMζ is a candidate molecule uniquely
important for information storage at synapses and during behavior.
Thus the overall goal of this application is to elucidate in mechanistic detail the function of PKMζ
in persistent synaptic enhancement and memory storage. Our 3 Specific Aims are: 1) To characterize
the mechanisms by which PKMζ enhances synaptic strength. We found that PKMζ potentiates synaptic
strength by increasing the number of postsynaptic AMPA receptors (AMPARs) through interactions
between the AMPAR GluR2 subunit and the trafficking protein NSF. We will examine whether this
potentiation is through increased exocytosis and/or decreased endocytosis of postsynaptic AMPARs
and the function of this altered trafficking in memory maintained by PKMζ. 2) To determine whether
preexisting and newly translated PKMζ mediate distinct phases of potentiation during LTP. Preliminary
evidence indicates that antisense oligodeoxynucleotides blocking new PKMζ synthesis prevents the
persistence of a phase of LTP. We will determine whether this new synthesis occurs at dendritic sites.
3) To determine the role of preexisting, newly translated, and new gene transcription of PKMζ in distinct
phase of memory. PKMζ maintains memory up to several months after training. We will employ both
antisense to block translation of PKMζ mRNA and conditional genetic deletion of PKMζ to examine the
function of distinct mechanisms of expression of PKMζ in different phases of memory. These 3 aims will
provide fundamental new information on a potential molecular mechanism for maintaining synaptic and
behavioral information storage, which may be relevant to both normal memory and its disorders.

## Key facts

- **NIH application ID:** 9942508
- **Project number:** 5R37MH057068-24
- **Recipient organization:** SUNY DOWNSTATE MEDICAL CENTER
- **Principal Investigator:** TODD C SACKTOR
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,750
- **Award type:** 5
- **Project period:** 2016-06-22 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942508

## Citation

> US National Institutes of Health, RePORTER application 9942508, Regulation and Neural Function of Atypical PKC (5R37MH057068-24). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9942508. Licensed CC0.

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