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

Neuron. 2021 Aug 18;109(16):2590-2603.e13. doi: 10.1016/j.neuron.2021.06.005. Epub 2021 Jun 30.

Authors

Dheeraj S Roy¹, Ying Zhang², Tomomi Aida², Soonwook Choi³, Qian Chen², Yuanyuan Hou², Nicholas E Lea², Keith M Skaggs², Juliana C Quay², Min Liew², Hannah Maisano², Vinh Le², Carter Jones³, Jie Xu⁴, Dong Kong⁴, Heather A Sullivan², Arpiar Saunders⁵, Steven A McCarroll⁵, Ian R Wickersham², Guoping Feng⁶

Affiliations

¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: droy@broadinstitute.org.
² McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA.
⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁶ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: fengg@mit.edu.

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.

Keywords: anterior thalamic nuclei; autism; cognition; memory; neuropsychiatric disorders; retrosplenial; schizophrenia; thalamus.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Anterior Thalamic Nuclei / physiology
Anterior Thalamic Nuclei / physiopathology*
Cerebral Cortex / physiopathology
Cognition / physiology
Cognitive Dysfunction / physiopathology*
Mice
Neural Pathways / physiology
Neural Pathways / physiopathology*
Thalamic Nuclei / physiology
Thalamic Nuclei / physiopathology*

Abstract

Publication types

MeSH terms

Grants and funding