Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality.
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.
1] Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan. [2].
Tzyy-Nan
TN
Huang
1] Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan. [2] Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. [3].
Hsiu-Chun
HC
Chuang
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Wen-Hsi
WH
Chou
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Chiung-Ya
CY
Chen
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Hsiao-Fang
HF
Wang
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
Shen-Ju
SJ
Chou
1] Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan. [2] Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Yi-Ping
YP
Hsueh
D000679:Amygdala / Q000473:pathology*; D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D058969:Contactin 2 / Q000378:metabolism; D003523:Cycloserine / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000172:deficiency*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D064326:MEF2 Transcription Factors / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000075385:Netrins; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D020825:T-Box Domain Proteins
D000963:Antimetabolites; D015820:Cadherins; C504541:Cdh8 protein, mouse; C548675:Cntn2 protein, mouse; D058969:Contactin 2; D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; D009419:Nerve Tissue Proteins; D000075385:Netrins; C456263:Ntng2 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D020825:T-Box Domain Proteins; C492271:Tbr1 protein, mouse; D003523:Cycloserine