# Probing schizophrenia associated neurodevelopmental defects in integrated neocortical organoids

> **NIH NIH F32** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $72,630

## Abstract

Abstract
Though Schizophrenia typically manifests during adolescence, evidence suggests that, for many patients, the
disorder originates during development. Perhaps one of the strongest indicators of this is the fact that cognitive
deficits, which represent a core component of the disease, are present in childhood, prior to the onset of the
“positive” and “negative” symptoms that will lead to a diagnosis of schizophrenia. The cognitive symptoms of
schizophrenia appear to be due to a defect in the GABAergic cells of the neocortex, cortical interneurons (cINs)
of the neocortex. In fact, reductions in the expression levels of GABAergic genes in the neocortex are among
the most consistently reported molecular defect in schizophrenia patients. Interestingly, evidence from human
and animal models suggest that cIN dysfunction within specific regions of the neocortex is the likely cause of the
cognitive deficits observed in schizophrenia patients. This raises the possibility that, in at least a subset of
patients, aberrations in cIN development may be to blame for the cognitive defects observed in schizophrenia.
Animal models of multiple schizophrenia-associated genomic structural variants have indicated that this may
indeed be the case. However, the precise nature of cIN developmental defects as they occur in schizophrenia
in humans is not known. The goal of the research project proposed herein is to unmask fundamental molecular
and cellular cIN deficiencies during neocortical development in a human integrated neocortical organoid.
 Integrated cortical organoids and spheroids hold the promise of modeling complex diseases in a 3D culture
which closely mimics the human cortex. The separate patterning and eventual aggregation of dorsal and ventral
forebrain organoids allows the ventral derived cINs to migrate into the dorsal forebrain organoid and integrate
with the locally born pyramidal neurons (PNs) in a manner analogous to how these structures develop in vivo. In
my first proposed aim of this study, I will use schizophrenia associated genomic structural variants to define
migration and distribution defects that occur during cIN integration into the dorsal forebrain in an integrated
neocortical organoid. As my final aim, I will utilize integrated neocortical organoids to uncover schizophrenia-
associated molecular defects present early in neurodevelopment which contribute to the disease. The completion
of the aims proposed in this project will lead to the establishment of a reliable in vitro model of the human
neocortex and provide potentially therapeutically relevant insights into aberrant development processes in
schizophrenia.

## Key facts

- **NIH application ID:** 10249989
- **Project number:** 5F32MH116590-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Ryan Walsh
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $72,630
- **Award type:** 5
- **Project period:** 2019-09-23 → 2022-09-22

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249989

## Citation

> US National Institutes of Health, RePORTER application 10249989, Probing schizophrenia associated neurodevelopmental defects in integrated neocortical organoids (5F32MH116590-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10249989. Licensed CC0.

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