Article

Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality

Nature Neuroscience (Impact Factor: 16.1). 01/2014; 17(2). DOI: 10.1038/nn.3626
Source: PubMed

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.

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    • "Tbr1 À/+ mice were used to investigate whether the loss of one allele results in autism-like phenotypes. Tbr1 haploinsufficiency resulted in reduced social interaction and vocalization, cognitive inflexibility and impaired associative memory (Huang et al. 2014). A well-known neuronal migration regulator is Reelin (RELN) (reviews Folsom and Fatemi 2012; Sekine et al. 2014). "
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    ABSTRACT: Autism Spectrum Disorders (ASD) encompass a group of neurodevelopmental diseases that demonstrate strong heritability, however the inheritance is not simple and many genes have been associated with these disorders. ASD is regarded as a neurodevelopmental disorder, and abnormalities at different developmental stages are part of the disease etiology. This review provides a general background on neuronal migration during brain development and discusses recent advancements in the field connecting ASD and aberrant neuronal migration. This article is protected by copyright. All rights reserved.
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    • "developmental condition ( Shukla et al . , 2010 ; Ingalhalikar et al . , 2011 ; Weinstein et al . , 2011 ) . Moreover , in mice Tbr1 haploinsufficiency also results in defective axonal projections of amygdalar neurons , which give rise to a deficit in ultrasonic vocalization , social interaction , and associative memory and cognitive flexibility ( Huang et al . , 2014 ) ."

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    • "developmental condition ( Shukla et al . , 2010 ; Ingalhalikar et al . , 2011 ; Weinstein et al . , 2011 ) . Moreover , in mice Tbr1 haploinsufficiency also results in defective axonal projections of amygdalar neurons , which give rise to a deficit in ultrasonic vocalization , social interaction , and associative memory and cognitive flexibility ( Huang et al . , 2014 ) ."
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