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 journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)2590-2603.e13
JournalNeuron
Volume109
Issue number16
DOIs
StatePublished - Aug 18 2021
Externally publishedYes

Keywords

  • anterior thalamic nuclei
  • autism
  • cognition
  • memory
  • neuropsychiatric disorders
  • retrosplenial
  • schizophrenia
  • thalamus

ASJC Scopus subject areas

  • Neuroscience(all)

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