Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality

Tzyy-Nan Huang; Hsiu-Chun Chuang; Wen-Hsi Chou; Chiung-Ya Chen; Hsiao-Fang Wang; Shen-Ju Chou; Yi-Ping Hsueh

doi:10.1038/nn.3626

Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality

Nat Neurosci. 2014 Feb;17(2):240-7. doi: 10.1038/nn.3626. Epub 2014 Jan 19.

Authors

Tzyy-Nan Huang¹, Hsiu-Chun Chuang², Wen-Hsi Chou³, Chiung-Ya Chen³, Hsiao-Fang Wang³, Shen-Ju Chou⁴, Yi-Ping Hsueh⁵

Affiliations

¹ 1] Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan. [2].
² 1] Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan. [2] Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. [3].
³ Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
⁴ Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
⁵ 1] Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan. [2] Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.

PMID: 24441682
DOI: 10.1038/nn.3626

Abstract

The neuron-specific transcription factor T-box brain 1 (TBR1) regulates brain development. Disruptive mutations in the TBR1 gene have been repeatedly identified in patients with autism spectrum disorders (ASDs). Here, we show that Tbr1 haploinsufficiency results in defective axonal projections of amygdalar neurons and the impairment of social interaction, ultrasonic vocalization, associative memory and cognitive flexibility in mice. Loss of a copy of the Tbr1 gene altered the expression of Ntng1, Cntn2 and Cdh8 and reduced both inter- and intra-amygdalar connections. These developmental defects likely impair neuronal activation upon behavioral stimulation, which is indicated by fewer c-FOS-positive neurons and lack of GRIN2B induction in Tbr1(+/-) amygdalae. We also show that upregulation of amygdalar neuronal activity by local infusion of a partial NMDA receptor agonist, d-cycloserine, ameliorates the behavioral defects of Tbr1(+/-) mice. Our study suggests that TBR1 is important in the regulation of amygdalar axonal connections and cognition.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amygdala / pathology*
Animals
Antimetabolites / therapeutic use
Axons / metabolism
Axons / pathology*
Cadherins / metabolism
Cognition Disorders / drug therapy
Cognition Disorders / genetics*
Cognition Disorders / pathology*
Contactin 2 / metabolism
Cycloserine / therapeutic use
DNA-Binding Proteins / deficiency*
Disease Models, Animal
Exploratory Behavior / physiology
Gene Expression Profiling
Gene Expression Regulation / genetics
MEF2 Transcription Factors / metabolism
Magnetic Resonance Imaging
Maze Learning / physiology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation / genetics
Nerve Tissue Proteins / metabolism
Netrins
Oligonucleotide Array Sequence Analysis
Organ Culture Techniques
Proto-Oncogene Proteins c-fos / metabolism
T-Box Domain Proteins

Substances

Antimetabolites
Cadherins
Cdh8 protein, mouse
Cntn2 protein, mouse
Contactin 2
DNA-Binding Proteins
MEF2 Transcription Factors
Nerve Tissue Proteins
Netrins
Ntng2 protein, mouse
Proto-Oncogene Proteins c-fos
T-Box Domain Proteins
Tbr1 protein, mouse
Cycloserine

Associated data

GEO/GSE49237