Tbr1autism mouse model displays altered structural and functional amygdalar connectivity and abnormal whole-brain synchronization

Abstract

AbstractAutism spectrum disorders (ASD) are recognized as neural disconnectivity syndromes. Here, we establish a whole-brain immunostaining and quantification platform to investigate structural and functional connectivity in aTbr1+/−autism mouse model, which shares a defect in the anterior commissure that is evolutionarily conserved with human patients. Since the basolateral amygdala (BLA) is particularly susceptible toTbr1haploinsufficiency and it projects to the contralateral brain hemisphere via the anterior commissure, we express a channelrhodopsin variant oChIEF fused with Citrine at the BLA to outline axonal projections of BLA neurons and to activate the BLA under blue light theta-burst stimulation (TBS). Next, we evaluate C-FOS expression to represent neural activity. We show thatTbr1haploinsufficiency almost completely disrupts contralateral BLA axonal projections and results in ipsilateral mistargeting, thereby globally altering BLA functional connectivity. Based on correlated C-FOS expression among brain regions, we further report thatTbr1deficiency severely disrupts whole-brain synchronization in the absence of salient stimulation.Tbr1+/−and wild-type mice exhibit opposing responses to TBS-induced amygdalar activation, with it reducing synchronization in wild-type mice but enhancing it inTbr1+/−mice. Whole-brain modular organization and inter-module connectivity are also affected by Tbr1 deficiency and amygdalar activation. In fact, the synchronization and intra- and inter-modular connectivities of TBS-treatedTbr1+/−mice are more comparable to those of non-treated wild-type mice, suggesting a potential ameliorating effect of amygdalar stimulation on brain function. Moreover,Tbr1+/−mice exhibit attenuated connectivity between the amygdala and default mode network, a subnetwork highly relevant to social behaviors, strengthening the link between the impaired connectivity and social behavior deficits displayed byTbr1+/−mice. Our high-resolution analytical platform reveals the inter- and intra-hemispheric connectopathies arising from an ASD condition and emphasizes the defective synchronization at a whole-brain scale caused byTbr1deficiency.