Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models

Dheeraj S. Roy; Ying Zhang; Tomomi Aida; Soonwook Choi; Qian Chen; Yuanyuan Hou; Nicholas E. Lea; Keith M. Skaggs; Juliana C. Quay; Min Liew; Hannah Maisano; Vinh Le; Carter Jones; Jie Xu; Dong Kong; Heather A. Sullivan; Arpiar Saunders; Steven A. McCarroll; Ian R. Wickersham; Guoping Feng

doi:10.1016/j.neuron.2021.06.005

Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models

Dheeraj S. Roy, Ying Zhang, Tomomi Aida, Soonwook Choi, Qian Chen, Yuanyuan Hou, Nicholas E. Lea, Keith M. Skaggs, Juliana C. Quay, Min Liew, Hannah Maisano, Vinh Le, Carter Jones, Jie Xu, Dong Kong, Heather A. Sullivan, Arpiar Saunders, Steven A. McCarroll, Ian R. Wickersham, Guoping Feng

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

Neuropsychiatric disorders are often accompanied by cognitive impairments/intellectual disability (ID). It is not clear whether there are converging mechanisms underlying these debilitating impairments. We found that many autism and schizophrenia risk genes are expressed in the anterodorsal subdivision (AD) of anterior thalamic nuclei, which has reciprocal connectivity with learning and memory structures. CRISPR-Cas9 knockdown of multiple risk genes selectively in AD thalamus led to memory deficits. While the AD is necessary for contextual memory encoding, the neighboring anteroventral subdivision (AV) regulates memory specificity. These distinct functions of AD and AV are mediated through their projections to retrosplenial cortex, using differential mechanisms. Furthermore, knockdown of autism and schizophrenia risk genes PTCHD1, YWHAG, or HERC1 from AD led to neuronal hyperexcitability, and normalization of hyperexcitability rescued memory deficits in these models. This study identifies converging cellular to circuit mechanisms underlying cognitive deficits in a subset of neuropsychiatric disease models.

Original language	English (US)
Pages (from-to)	2590-2603.e13
Journal	Neuron
Volume	109
Issue number	16
DOIs	https://doi.org/10.1016/j.neuron.2021.06.005
State	Published - Aug 18 2021
Externally published	Yes

Keywords

anterior thalamic nuclei
autism
cognition
memory
neuropsychiatric disorders
retrosplenial
schizophrenia
thalamus

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2021.06.005

Cite this

Roy, D. S., Zhang, Y., Aida, T., Choi, S., Chen, Q., Hou, Y., Lea, N. E., Skaggs, K. M., Quay, J. C., Liew, M., Maisano, H., Le, V., Jones, C., Xu, J., Kong, D., Sullivan, H. A., Saunders, A., McCarroll, S. A., Wickersham, I. R., & Feng, G. (2021). Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models. Neuron, 109(16), 2590-2603.e13. https://doi.org/10.1016/j.neuron.2021.06.005

Roy, DS, Zhang, Y, Aida, T, Choi, S, Chen, Q, Hou, Y, Lea, NE, Skaggs, KM, Quay, JC, Liew, M, Maisano, H, Le, V, Jones, C, Xu, J, Kong, D, Sullivan, HA, Saunders, A, McCarroll, SA, Wickersham, IR & Feng, G 2021, 'Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models', Neuron, vol. 109, no. 16, pp. 2590-2603.e13. https://doi.org/10.1016/j.neuron.2021.06.005

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title = "Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models",

abstract = "Neuropsychiatric disorders are often accompanied by cognitive impairments/intellectual disability (ID). It is not clear whether there are converging mechanisms underlying these debilitating impairments. We found that many autism and schizophrenia risk genes are expressed in the anterodorsal subdivision (AD) of anterior thalamic nuclei, which has reciprocal connectivity with learning and memory structures. CRISPR-Cas9 knockdown of multiple risk genes selectively in AD thalamus led to memory deficits. While the AD is necessary for contextual memory encoding, the neighboring anteroventral subdivision (AV) regulates memory specificity. These distinct functions of AD and AV are mediated through their projections to retrosplenial cortex, using differential mechanisms. Furthermore, knockdown of autism and schizophrenia risk genes PTCHD1, YWHAG, or HERC1 from AD led to neuronal hyperexcitability, and normalization of hyperexcitability rescued memory deficits in these models. This study identifies converging cellular to circuit mechanisms underlying cognitive deficits in a subset of neuropsychiatric disease models.",

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author = "Roy, {Dheeraj S.} and Ying Zhang and Tomomi Aida and Soonwook Choi and Qian Chen and Yuanyuan Hou and Lea, {Nicholas E.} and Skaggs, {Keith M.} and Quay, {Juliana C.} and Min Liew and Hannah Maisano and Vinh Le and Carter Jones and Jie Xu and Dong Kong and Sullivan, {Heather A.} and Arpiar Saunders and McCarroll, {Steven A.} and Wickersham, {Ian R.} and Guoping Feng",

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AU - Quay, Juliana C.

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AU - Maisano, Hannah

AU - Le, Vinh

AU - Jones, Carter

AU - Xu, Jie

AU - Kong, Dong

AU - Sullivan, Heather A.

AU - Saunders, Arpiar

AU - McCarroll, Steven A.

AU - Wickersham, Ian R.

AU - Feng, Guoping

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N2 - Neuropsychiatric disorders are often accompanied by cognitive impairments/intellectual disability (ID). It is not clear whether there are converging mechanisms underlying these debilitating impairments. We found that many autism and schizophrenia risk genes are expressed in the anterodorsal subdivision (AD) of anterior thalamic nuclei, which has reciprocal connectivity with learning and memory structures. CRISPR-Cas9 knockdown of multiple risk genes selectively in AD thalamus led to memory deficits. While the AD is necessary for contextual memory encoding, the neighboring anteroventral subdivision (AV) regulates memory specificity. These distinct functions of AD and AV are mediated through their projections to retrosplenial cortex, using differential mechanisms. Furthermore, knockdown of autism and schizophrenia risk genes PTCHD1, YWHAG, or HERC1 from AD led to neuronal hyperexcitability, and normalization of hyperexcitability rescued memory deficits in these models. This study identifies converging cellular to circuit mechanisms underlying cognitive deficits in a subset of neuropsychiatric disease models.

AB - Neuropsychiatric disorders are often accompanied by cognitive impairments/intellectual disability (ID). It is not clear whether there are converging mechanisms underlying these debilitating impairments. We found that many autism and schizophrenia risk genes are expressed in the anterodorsal subdivision (AD) of anterior thalamic nuclei, which has reciprocal connectivity with learning and memory structures. CRISPR-Cas9 knockdown of multiple risk genes selectively in AD thalamus led to memory deficits. While the AD is necessary for contextual memory encoding, the neighboring anteroventral subdivision (AV) regulates memory specificity. These distinct functions of AD and AV are mediated through their projections to retrosplenial cortex, using differential mechanisms. Furthermore, knockdown of autism and schizophrenia risk genes PTCHD1, YWHAG, or HERC1 from AD led to neuronal hyperexcitability, and normalization of hyperexcitability rescued memory deficits in these models. This study identifies converging cellular to circuit mechanisms underlying cognitive deficits in a subset of neuropsychiatric disease models.

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Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models

Abstract

Keywords

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