# Gyrencephalic Model for Neurodevelopmental Disease and Postnatal Cortical Therapeutic Interventions

> **NIH NIH DP2** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $2,422,500

## Abstract

PROJECT SUMMARY
Cortical inhibitory neurons (CIN) are a neuronal subpopulation that have been strongly implicated in the
pathogenesis of neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD)1. We
recently published evidence of robust CIN migration in the postnatal human brain2, in a population called the
Arc, that contributes to the cortical network in the prefrontal cortex and cingulate during the first months of life.
The presence of this migratory population demonstrates that the human cortex remains dynamic in the
perinatal period, the time before and after birth, and raised the need to find methods to interrogate the
functional importance of “late-migrating” neurons. Perinatal human cortical development, however, is
incompletely represented in the lissencephalic (agyric) rodent brain and brain tissues from this period are
scarce. This has left a fundamental gap in human developmental neuroscience. The long-term goal of my
research is to understand the development of the gyrated neocortex during the perinatal period, the weeks
immediately before and after birth, and how disruption during that time can lead to neuropsychiatric conditions
such as ASD. Our central hypothesis is that CIN continue to travel perinatally to multiple cortical regions, and
that disruption of this migration contributes to abnormal social behaviors, a hallmark phenotype in ASD. To test
this, we will develop the piglet cortex, which closely mimics the human neocortex, as a model to investigate the
molecular diversity of CIN migrating in the perinatal brain. We will also perform birthdating experiments to
determine if postnatal stem cell divisions continue to generate CIN after birth. Lastly, we will generate a
conditional piglet model that specifically removes expression of the Reelin receptor, (very low density
lipoprotein receptor) VLDLR, implicated in ASD etiology3,4, within a subpopulation of “late-migrating” CIN. The
cellular and behavioral consequences of interrupting Reelin signaling will be examined. The proposed studies
will identify distinctive properties of migratory CIN and aim to establish a novel approach to investigate ASD.
By creating a more faithful model of the human cortex, we can establish the cellular processes that are needed
late in cortical development and identify new ways to therapeutically influence nerve cells, even after birth.

## Key facts

- **NIH application ID:** 10002558
- **Project number:** 1DP2NS122550-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Mercedes Paredes
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,422,500
- **Award type:** 1
- **Project period:** 2020-09-30 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002558

## Citation

> US National Institutes of Health, RePORTER application 10002558, Gyrencephalic Model for Neurodevelopmental Disease and Postnatal Cortical Therapeutic Interventions (1DP2NS122550-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10002558. Licensed CC0.

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