Determining Changes in Neural Circuits in Tuberous Sclerosis.

摘要

The purpose of our research proposal is to unravel how neural circuits and neuronal physiology of the thalamus contribute to brain dysfunction in Tuberous Sclerosis. Using a novel genetic circuit mapping approach along with temporal gene deletion we were able to ascertain the temporal role of Tsc1 in establishing thalamocortical circuitry and to determine how Tsc1 loss during embryonic development impacts thalamocortical circuit function. Specifically, we show that deletion of Tsc1 during a discrete time window results in ectopic parvalbumin-expressing thalamic neurons and their axons that exit the thalamus and do not properly innervate the somatosensory cerebral cortex, which is a direct target of thalamocortical circuits. The aberrant thalamus to cortex circuit was accompanied by a secondary patterning defect in the somatosensory cortex, which demonstrates a cell non-autonomous component accompanies the primary genetic lesion. These alterations cause excessive repetitive grooming and robust seizures that were present in all eleven conditional mutant mice. We also show that thalamic neurons have enlarged soma and concomitant alterations in intrinsic membrane properties (membrane capacitance and input resistance) and have disrupted firing properties in both the burst and tonic firing modes. Finally, we report that global neural networks in somatosensory cortex are altered as determined by recording by local field potentials. The major findings during the entire research period are that we identified a critical developmental window during which Tsc1 deletion in the embryonic thalamus causes deficits in thalamocortical neural circuit architecture, altered electrophysiological properties of neurons, and behavioral abnormalities. Thus, Tsc1 deletion in the thalamus mimicked salient features of human Tuberous Sclerosis including mosaicism, autism and epilepsy.