Individually mutated neurons ensnare the neocortex into hyperexcitable networks, as evidenced by abnormal LFPs in SI. Thus, disruption of an anatomically distinct but functionally

connected node within a circuit can propagate the disease phenotype. Comparing the effects of early and late Tsc1 deletion is informative. We did not detect abnormal physiological properties of Tsc1ΔE18/ΔE18 VB neurons, which indicates that, at least for VB neurons, there is a critical window of Tsc1/mTOR required to establish proper intrinsic excitability properties. Nevertheless, a striking finding is that neocortical (SI) Proteasome inhibitor LFP activity was altered in some E18.5 deletion animals. The most likely reason for the global abnormalities is that feedback loops involving multiple thalamic nuclei have altered physiology, which

is propagated both locally and to other brain regions. The sources of altered feedback may involve thalamic nuclei that undergo substantial recombination at E18.5 (such as Po) and that subsequently disrupt the reticulothalamic or the corticothalamic loops. By comparing the early versus later deletion of Tsc1, we are able to discern that abnormalities, even in a small proportion of cells, can cause reverberating global changes in neural activity. Comparison of our thalamic Tsc1 mutant phenotypes to other mouse models can be informative in considering the contribution of individual brain regions to global neural dysfunction.

Behaviorally, Tsc1ΔE12/ΔE12 animals groomed excessively, to the extent that they Inhibitor Library gave themselves severe lesions. A similar overgrooming phenotype has been described in genetic mouse models of autism and obsessive compulsive disorder in which Slitrk5, Shank3, or Sapap3 is deleted ( Welch et al., 2007; Shmelkov et al., 2010; Peça et al., 2011). Because striatum-specific gene rescue can ameliorate the phenotype, these groups implicate the corticostriatal circuit in causing abnormal repetitive behaviors. The thalamus projects both directly and indirectly, via neocortex, to the striatum ( Smith et al., 2004), suggesting that abnormal no thalamic modulation of the striatum in our mice contributes to the repetitive grooming phenotype. However, it is possible that sparse recombination in other subcortical brain structures, such as the striatum and hindbrain, may also contribute to the behavioral changes. Tsc1 or Tsc2 knockout in Purkinje cells of the cerebellum also causes repetitive grooming ( Tsai et al., 2012; Reith et al., 2013), possibly by disrupting signals from the cerebellum to the motor cortex, which are relayed by the ventrolateral thalamus. In addition, all Tsc1ΔE12/ΔE12 and some Tsc1ΔE18/ΔE18 mice experience seizures and abnormal neural activity with epileptiform features. Seizures are a common feature of TS clinically. Tsc1 knockout in forebrain neurons leads to seizures in 10% of mice ( Meikle et al.