# Synaptic plasticity mechanisms that protect and refine local circuits

> **NIH NIH R56** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $466,757

## Abstract

ABSTRACT
Synapses form trillions of connections between billions of neurons in the brain to establish neural circuits that
allow us to sense, think, act, learn, and remember. Our goal is to understand how synapse structure supports
learning and memory with a focus on dendritic spines, the tiny protrusions that host most of the excitatory
synapses in the brain. While most neuroscientists would agree that synapse growth and retraction are vital for
learning and memory, we do not know how these long-term changes in synaptic structure are regulated in the
face of ongoing brain plasticity. The synaptic active zone comprises discrete domains where presynaptic
vesicles are docked and released. Postsynaptic responses are restricted to regions within ~100 nm of the
vesicle release sites. Our three-dimensional reconstruction from serial section electron microscopy (3DEM)
reveals three zones across the synapse: (i) strong active zones (AZs) that have tightly docked presynaptic
vesicles, (ii) weak AZs that have loose or nondocked presynaptic vesicles, and (iii) nascent zones (NZs) that
have a thick postsynaptic density but no presynaptic vesicles. At the onset of long-term potentiation (LTP),
presynaptic vesicles are rapidly recruited to the NZs, converting them to AZs. Protein filaments shorten and
draw docked presynaptic vesicles closer to the enlarged AZs, and recruit vesicles to dock at weak AZs. This
evidence of presynaptic plasticity would increase the area of release and probability of postsynaptic receptor
response. The recovery interval following saturation of LTP is 1-4 hours depending on the preparation. During
this interval, new NZs form, primarily on spines containing smooth endoplasmic reticulum, a local resource for
regulating calcium and trafficking of lipids, proteins, and organelles. Clusters of spines form in the vicinity of
these enlarged spines. We hypothesize that synapse-specific expansion of NZs during LTP provides a basis
for learning and the advantage of spaced over massed learning to establish long-lasting memories.
Furthermore, we hypothesize that LTD is driven by the conversion of weak AZs to NZs and ultimately
elimination of spines without AZs. To address these hypotheses, we propose multidisciplinary approaches to
investigate NZ and AZ plasticity—including slice physiology, optogenetics, glutamate uncaging, and
tomographic 3DEM of synapses along activated axons labeled with APEX. Our Specific Aims are: Aim 1)
Determine the specificity of NZ to AZ conversion during synapse enlargement, resource utilization, and spine
clustering underlying the saturation, recovery, and enhancement of LTP. Aim 2) Test whether saturating LTP
at an isolated dendritic spine is sufficient to fill NZs and determine the role of PSD-MAGUK proteins and their
interaction partners in the recovery of LTP from saturation. Aim 3) Test whether saturation of long-term
depression (LTD) is accompanied by loss of weak AZs and determine the time-course over which LT...

## Key facts

- **NIH application ID:** 11126361
- **Project number:** 1R56MH139176-01
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** KRISTEN M HARRIS
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $466,757
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11126361

## Citation

> US National Institutes of Health, RePORTER application 11126361, Synaptic plasticity mechanisms that protect and refine local circuits (1R56MH139176-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11126361. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*