The activity-regulated gene expression of transcription factors is required for 
neural plasticity and function in response to neuronal stimulation. T-brain-1 
(TBR1), a critical neuron-specific transcription factor for forebrain 
development, has been recognized as a high-confidence risk gene for autism 
spectrum disorders. Here, we show that in addition to its role in brain 
development, Tbr1 responds to neuronal activation and further modulates the 
Grin2b expression in adult brains and mature neurons. The expression levels of 
Tbr1 were investigated using both immunostaining and quantitative reverse 
transcription polymerase chain reaction (RT-PCR) analyses. We found that the 
mRNA and protein expression levels of Tbr1 are induced by excitatory synaptic 
transmission driven by bicuculline or glutamate treatment in cultured mature 
neurons. The upregulation of Tbr1 expression requires the activation of both 
α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and 
N-methyl-D-aspartate (NMDA) receptors. Furthermore, behavioral training triggers 
Tbr1 induction in the adult mouse brain. The elevation of Tbr1 expression is 
associated with Grin2b upregulation in both mature neurons and adult brains. 
Using Tbr1-deficient neurons, we further demonstrated that TBR1 is required for 
the induction of Grin2b upon neuronal activation. Taken together with the 
previous studies showing that TBR1 binds the Grin2b promoter and controls 
expression of luciferase reporter driven by Grin2b promoter, the evidence 
suggests that TBR1 directly controls Grin2b expression in mature neurons. We 
also found that the addition of the calcium/calmodulin-dependent protein kinase 
II (CaMKII) antagonist KN-93, but not the calcium-dependent phosphatase 
calcineurin antagonist cyclosporin A, to cultured mature neurons noticeably 
inhibited Tbr1 induction, indicating that neuronal activation upregulates Tbr1 
expression in a CaMKII-dependent manner. In conclusion, our study suggests that 
Tbr1 plays an important role in adult mouse brains in response to neuronal 
activation to modulate the activity-regulated gene transcription required for 
neural plasticity.