# Development of Visual Connections

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $412,805

## Abstract

7. Project Summary
What enables a baby's brain to learn so rapidly during early developmental critical periods? Is it possible to re-
engage in adult the enhanced learning capacity present in the child's brain for repair or restoration of function?
We have discovered that a neuronal receptor called PirB (Paired Immunoglobulin-like receptor B; human
LilrB2/3) regulates synapse pruning and plasticity in cerebral cortex. Blocking PirB function in visual cortex
rapidly leads to new dendritic spines and functional synapses even in adult. These observations have clinical
relevance. A hallmark of Alzheimer's disease (AD) is loss of plasticity and excessive synapse pruning. But
when PirB is knocked out in a mouse model of AD, mice are protected from memory loss. Moreover, new
synapses generated by PirB blockade can be captured to facilitate recovery from severe vision loss in
Amblyopia. A major goal of this research proposal is to save or regenerate synapses by understanding cell and
molecular mechanisms of how PirB regulates synapse pruning. Three specific aims are proposed. 1) Assess
effects of PirB deletion on dendritic spine density and stability in visual cortex. We have generated mice with a
conditional allele of PirB (PirB flox/flox). We have also made a soluble PirB function- blocking recombinant
protein: sPirB. These mice and reagents permit cell-type specific and temporal disruption of PirB and will be
used in 2 photon imaging and physiological studies of synapse pruning and spine turnover in cortical pyramidal
neurons. Results from these experiments should illuminate further how PirB regulates plasticity and synapse
pruning in juvenile and adult visual cortex. 2) Investigate how PirB functions by using expression profiling to
identify PirB signaling pathways. Preliminary experiments suggest that cofilin signaling contributes to PirB
dependent regulation of dendritic spine density, and is hyperactivated in a mouse model of AD. Here an
unbiased approach to identify PirB-driven alterations in mRNA expression is proposed. RiboTag mice will be
used to isolate neuronal transcripts from PirB+/+ vs PirB-/- visual cortex. Using microarrays and RNAseq, the
transcriptomes of the 2 genotypes will be analyzed and compared. This approach should facilitate identification
of candidate signaling pathways regulated by PirB. 3) PirB and Alzheimer's disease- Engineer high affinity,
specific blockers of the PirB-Abeta interaction. We have measured a direct interaction between PirB and
soluble oligomers of beta amyloid (Abeta), the pathogenic 42 amino acid peptide in AD. The PirB-Abeta
interaction represents a novel and potentially pivotal signaling axis. Protein engineering techniques including
yeast display and affinity maturation will be used to create molecular entities able to block the Abeta-PirB (or
Abeta-LilrB2 in human) interaction, potentially yielding new drug targets to treat AD. In sum, this proposal
seeks to extend understanding of PirB function and d...

## Key facts

- **NIH application ID:** 9915921
- **Project number:** 5R01EY002858-43
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Carla J Shatz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,805
- **Award type:** 5
- **Project period:** 1979-01-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9915921

## Citation

> US National Institutes of Health, RePORTER application 9915921, Development of Visual Connections (5R01EY002858-43). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9915921. Licensed CC0.

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