, 2002). Widespread deletion of Tsc1 in neural progenitors has also been shown to cause spontaneous seizures in adult mice ( Goto et al., 2011). Ours, however, is a conditional Tsc1 knockout that causes both seizures and overgrooming. Although one may presume that this is simply because Selleckchem HIF inhibitor the thalamus is a central structure

and its dysregulation therefore compromises multiple functional circuits, the explanation cannot be that simple; in the Meikle et al. and Goto et al. studies, Tsc1 recombination occurs in the thalamus as well as the rest of the forebrain. The fact that more comprehensive Tsc1 knockouts do not produce similar overgrooming suggests that perturbing a single node of a neural network has the potential to be more deleterious than disrupting the entire network, perhaps because global homeostatic mechanisms are not invoked when only part of a highly interconnected and integrative system is dysregulated. This is an important consideration for brain structures, such as the thalamus, which feature complex feedback loops and widespread reciprocal connectivity that could amplify and spread the effects of a slight functional imbalance. This concept

is particularly relevant given click here the mosaic nature of TS in humans, in which subsets of cells undergo biallelic TSC1/2 mutations, leading to discrete cohorts of mutant cells ( Crino et al., 2010). It is important to note, however, that while thalamic Tsc1 knockout replicates salient features of TS, we are not implying that TS is a disease of the thalamus. Rather, our findings suggest that the thalamus and other subcortical regions warrant further investigation and that the complex nature of disorders like TS involve multiple brain regions that may respond differentially to the same genetic

insult. The phenotypes related to E12.5 versus E18.5 Tsc1 inactivation suggest three contributing factors: the spatial pattern of recombination, the overall number of affected cells, and the developmental timing of Tsc1 inactivation. The spatial pattern of recombination is clearly important and experimentally arises from the dynamic expression of the Gbx2 gene regulatory elements that drive Non-specific serine/threonine protein kinase CreER expression ( Chen et al., 2009). The dynamic recombination pattern causes the MD, MG, and AM nuclei to undergo recombination at both E12.5 and E18.5. In contrast, the Pf and VB nuclei are largely spared by recombination at E18.5. This differential involvement of nuclei probably leads to distinct consequences. The Pf and VB nuclei project, either directly or indirectly, to the dorsolateral striatum ( Pan et al., 2010), which is a central component in a circuit that regulates a syntactic chain of grooming behaviors ( Cromwell and Berridge, 1996). Disruption of this circuit at E12.5, but not at E18.5, could underlie the compulsive grooming behavior in Tsc1ΔE12/ΔE12, but not Tsc1ΔE18/ΔE18, mutant animals.