Kurzfassung

The mTOR (mechanistic target of rapamycin) kinase is the most important regulator of local dendritic and perisynaptic protein translation in the brain. Both, loss and gain of mTOR activity lead to significant disturbances of brain homeostasis and neuronal function resulting in intellectual disability(ID), epilepsy and behavioral alterations.
 
Based on the fundamental role that mTOR kinase plays in synaptic protein synthesis and our preliminary results, we hypothesize that mTOR dysfunction...The mTOR (mechanistic target of rapamycin) kinase is the most important regulator of local dendritic and perisynaptic protein translation in the brain. Both, loss and gain of mTOR activity lead to significant disturbances of brain homeostasis and neuronal function resulting in intellectual disability(ID), epilepsy and behavioral alterations.
 
Based on the fundamental role that mTOR kinase plays in synaptic protein synthesis and our preliminary results, we hypothesize that mTOR dysfunction leads to a set point shiftand significantly influences neuronal homeostasis by altering cell excitability, E/I balance, synaptic connectivity and plasticity.
 
In the proposedproject we will use two different mouse models:on one hand, Tsc2+/- animals carry a heterozygous mutation in the mTOR inhibitor gene Tcs2 that leads to chronic hyperactivity of mTOR. On the other hand, Mid1-/y and Mid2-/y double knock-out mice carry mutations in mTOR activating genes andpresent with reduced mTOR activity. We will combine excitability measurements and electrophysiological analysis of E/I balance in-vitro and in-vivo with outcomes of cognitive behavior.
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