Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality
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.
- SourceAvailable from: Antonio Benítez-Burraco
[Show abstract] [Hide abstract]
- "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 ) ."
ABSTRACT: The sequencing of the genomes from extinct hominins has revealed that changes in some brain-related genes have been selected after the split between anatomically-modern humans and Neanderthals/Denisovans. To date, no coherent view of these changes has been provided. Following a line of research we initiated in Boeckx and Benítez-Burraco (2014a), we hypothesize functional links among most of these genes and their products, based on the existing literature for each of the gene discussed. The genes we focus on are found mutated in different cognitive disorders affecting modern populations and their products are involved in skull and brain morphology, and neural connectivity. If our hypothesis turns out to be on the right track, it means that the changes affecting most of these proteins resulted in a more globular brain and ultimately brought about modern cognition, with its characteristic generativity and capacity to form and exploit cross-modular concepts, properties most clearly manifested in language.Frontiers in Psychology 06/2015; 6:794. DOI:10.3389/fpsyg.2015.00794 · 2.80 Impact Factor
[Show abstract] [Hide abstract]
- "Abnormalities in activity-regulated transcriptional pathways have been implicated in neurodevelopmental disorders (Pfeiffer et al., 2010; King et al., 2013), especially in autism spectrum disorders (ASDs), which are characterized by deficits in social interaction and communication, cognitive inflexibility, repetitive behaviors, and intellectual disability. Recent genetic studies have found recurrent mutations of T-brain-1 (TBR1), encoding a brain-specific T-box transcription factor (Bulfone et al., 1995), in ASD patients and identified Tbr1 as a causative gene in ASDs (Neale et al., 2012; O’Roak et al., 2012a; Huang et al., 2014). "
ABSTRACT: 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 (ASDs). 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 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 AMPA and 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 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 pFrontiers in Cellular Neuroscience 09/2014; 8:280. DOI:10.3389/fncel.2014.00280 · 4.18 Impact Factor
[Show abstract] [Hide abstract]
- "Through development, the wiring of the cortex is refined to receive and establish both local (Callaway, 1998; Fino and Yuste, 2011; Kä tzel et al., 2011; Ko et al., 2011; Kozloski et al., 2001; Yoshimura et al., 2005) and long-range (Berezovskii et al., 2011; Salin and Bullier, 1995) projections that convey information for multimodal integration (Iurilli et al., 2012; Mao et al., 2011) and normal cognitive function (Huang et al., 2014; Reis Marques et al., 2014; Zhang et al., 2014). In many sensory cortical areas, the final organization of the network contains reoccurring features that include dedicated cortico-cortical (CC) versus cortico-thalamic (CT) projection pathways formed by the principal cells found in deep layer six (L6) (Kumar and Ohana, 2008; Marx and Feldmeyer , 2013; Pichon et al., 2012; Thomson, 2010; Zhang and Deschê nes, 1997). "
ABSTRACT: Sensory computations performed in the neocortex involve layer six (L6) cortico-cortical (CC) and cortico-thalamic (CT) signaling pathways. Developing an understanding of the physiological role of these circuits requires dissection of the functional specificity and connectivity of the underlying individual projection neurons. By combining whole-cell recording from identified L6 principal cells in the mouse primary visual cortex (V1) with modified rabies virus-based input mapping, we have determined the sensory response properties and upstream monosynaptic connectivity of cells mediating the CC or CT pathway. We show that CC-projecting cells encompass a broad spectrum of selectivity to stimulus orientation and are predominantly innervated by deep layer V1 neurons. In contrast, CT-projecting cells are ultrasparse firing, exquisitely tuned to orientation and direction information, and receive long-range input from higher cortical areas. This segregation in function and connectivity indicates that L6 microcircuits route specific contextual and stimulus-related information within and outside the cortical network.Neuron 08/2014; 83(6). DOI:10.1016/j.neuron.2014.08.001 · 15.98 Impact Factor