SUMMARY Tuberous Sclerosis is a developmental genetic disorder caused by mutations in TSC1, which results in epilepsy, autism, and intellectual disability. The cause of these neurological deficits remains unresolved. Imaging studies suggest the thalamus may be affected in Tuberous Sclerosis patients, but this has not been experimentally interrogated. We hypothesized that thalamic deletion of Tsc1 at distinct stages of brain development would produce differential phenotypes. We show that mosaic Tsc1 deletion within thalamic precursors at embryonic day (E)12.5 disrupts thalamic circuitry and alters neuronal physiology. Tsc1 deletion at this early stage is unique in causing both seizures and compulsive grooming in adult mice. Only a subset of these phenotypes occurs when thalamic Tsc1 is deleted at a later embryonic stage. Our findings demonstrate that abnormalities in a discrete population of neurons can cause global brain dysfunction and that phenotype severity depends on developmental timing and degree of genetic mosaicism.
Most sensory information destined for the neocortex is relayed through the thalamus, where considerable transformation occurs 1 , 2 . One powerful means of transformation involves interactions between excitatory thalamocortical neurons that carry data to cortex and inhibitory neurons of the thalamic reticular nucleus (TRN) that regulate flow of those data 3 – 6 . Despite enduring recognition of its importance 7 – 9 , understanding of TRN cell types, their organization, and their functional properties has lagged that of the thalamocortical systems they control. Here we address this, investigating somatosensory and visual circuits of the TRN. In the somatosensory TRN we observed two groups of genetically defined neurons that are topographically segregated, physiologically distinct, and connect reciprocally with independent thalamocortical nuclei via dynamically divergent synapses. Calbindin-expressing cells, located in the central core, connect with the ventral posterior nucleus (VP), the primary somatosensory thalamocortical relay. In contrast, somatostatin-expressing cells, residing along the surrounding edges of TRN, synapse with the posterior medial thalamic nucleus (POM), a higher-order structure that carries both top-down and bottom-up information 10 – 12 . The two TRN cell groups process their inputs in pathway-specific ways. Synapses from VP to central TRN cells transmit rapid excitatory currents that depress deeply during repetitive activity, driving phasic spike output. Synapses from POM to edge TRN cells evoke slower, less depressing excitatory currents that drive more persistent spiking. Differences in intrinsic physiology of TRN cell types, including state-dependent bursting, contribute to these output dynamics. Thus, processing specializations of two somatosensory TRN subcircuits appear to be tuned to the signals they carry—a primary central subcircuit to discrete sensory events, and a higher-order edge subcircuit to temporally distributed signals integrated from multiple sources. The structure and function of visual TRN subcircuits closely resemble those of the somatosensory TRN. These results provide fundamental insights about how subnetworks of TRN neurons may differentially process distinct classes of thalamic information.
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