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Modeling ASD-linked genetic mutations in 3D human brain organoids

Award Number: R01MH112940
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Modeling ASD-linked genetic mutations in 3D human brain organoids - Project summary / Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose underlying mechanisms have been proposed to include abnormal excitatory-inhibitory balance in brain regions including the cerebral cortex. The ATP-dependent chromatin-remodeling factor chromodomain helicase binding protein 8 (CHD8) is one of the most commonly-mutated genes in sporadic ASD, producing an ASD subtype associated with a high prevalence of macrocephaly (Barnard et al., Front Neurosci., 2015). In prior work supported by the original grant, we optimized a human cortical organoid model we developed (Velasco et al., Nature, 2019; Uzquiano et al., Cell, 2022) and applied it to show that CHD8 and other ASD risk genes converge on an early developmental defect in the GABAergic neuron lineage, leading to asynchronous development of target neurons relative to the other cell types developing in the organoids (Paulsen et al., Nature, 2022). From this data, we hypothesized that asynchronous development of GABAergic neurons relative to the excitatory neurons they wire with could lead to later abnormalities in the activity and function of the cortical local circuit. In support of this hypothesis, we showed that mutation in another ASD risk gene, SUV420H1, also associated with accelerated development of GABAergic neurons, leads to abnormal activity of mutant circuits in organoids (Paulsen et al., Nature, 2022). Building on this data, in this renewal we will leverage our expertise in organoid biology and cortical development together with co-Investigator Mark Harnett's expertise in human cortical physiology to investigate the effect of heterozygous loss-of-function of CHD8 on neuronal development and circuit activity using newly-developed organoid models. Firstly, we will apply a chimeric organoid (“chimeroid”) model (Antón Bolaños and Faravelli et al., preprint at bioRxiv 2023, and in revision at Nature) to understand whether the genetic context of ASD patients is permissive for expressivity of the previously-identified CHD8+/- phenotypes (Aim 1). In parallel, we will apply a new human organoid model of the ventral telencephalon, which we validated to be able to produce GABAergic neurons of the caudal, medial, and lateral ganglionic eminences (Sartore et al., manuscript in preparation), to understand whether specific classes of GABAergic interneurons are preferentially affected by CHD8 mutation (Aim 2). Finally, with the aim of promoting circuits that reflect the endogenous neuronal composition, we will apply a new “dorsal-ventral chimeroid” organoid model that allows us to control development of the correct proportions of both excitatory and inhibitory cortical neurons, to investigate cell identity and circuit activity in the CHD8 heterozygous mutant in a more physiologically-relevant system, using calcium imaging, extracellular recording, and pharmacological manipulations (Aim 3). Taken together, this work will provide mechanistic understanding of the roles of a major ASD risk gene in the formation of GABAergic neuron populations of the cerebral cortex and in the biology of cortical circuits.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $832,293 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Mental Health Research Grants	001	7	7/14/2025	NON-COMPETING CONTINUATION	$832,293
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Mental Health Research Grants	000	6	10/11/2024	COMPETING CONTINUATION	$0
														Subtotal = $832,293

Issue Date FY: 2024 ( Subtotal = $841,300 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Mental Health Research Grants	001	6	9/4/2024	COMPETING CONTINUATION	$849,543
2024	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Mental Health Research Grants	000	5	1/18/2024	NON-COMPETING CONTINUATION	-$8,243
														Subtotal = $841,300

Issue Date FY: 2022 ( Subtotal = $515,135 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Mental Health Research Grants	000	5	11/10/2021	NON-COMPETING CONTINUATION	$463,621
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Mental Health Research Grants	001	5	5/12/2022	NON-COMPETING CONTINUATION	$51,514
														Subtotal = $515,135

Issue Date FY: 2021 ( Subtotal = $517,884 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Mental Health Research Grants	000	4	11/27/2020	NON-COMPETING CONTINUATION	$466,095
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Mental Health Research Grants	001	4	4/12/2021	NON-COMPETING CONTINUATION	$51,789
														Subtotal = $517,884

Issue Date FY: 2020 ( Subtotal = $520,630 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Mental Health Research Grants	000	3	1/18/2020	NON-COMPETING CONTINUATION	$520,630
														Subtotal = $520,630

Issue Date FY: 2019 ( Subtotal = $523,379 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Mental Health Research Grants	000	2	11/29/2018	NON-COMPETING CONTINUATION	$523,379
														Subtotal = $523,379

Issue Date FY: 2018 ( Subtotal = $571,066 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Mental Health Research Grants	000	1	1/22/2018	NEW	$571,066
														Subtotal = $571,066

Grand Total All Awards = $4,321,687

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Modeling ASD-linked genetic mutations in 3D human brain organoids

Award Number: R01MH112940

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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