Tuberous sclerosis complex (TSC) is an inherited disorder caused by mutations in the TSC1 and TSC2 genes. TSC is characterized by widespread formation of benign tumors in organs throughout the body, but affected persons also typically suffer from disabling neurological complications, including mental retardation, autism and a high incidence of epilepsy. Epilepsy occurs in 80% to 90% of TSC patients and two-thirds do not respond to available anti-seizure medication. Uncontrolled seizures contribute significantly to morbidity and mortality among TSC patients. Therefore, there is a pressing need to improve our understanding of the mechanisms underlying the development of epilepsy (epileptogenesis) in persons with TSC so as to guide the design of new drugs. Specifically, we wish to understand the pathological process by which a normal brain is transformed into an epileptic brain. While previous studies have mainly focused on brain cells such as neurons and astrocytes, research in my laboratory has revealed that another type of brain cell, called microglia, appears to play a significant role in epileptogenesis. We found that deleting the TSC1 gene in microglia in a mouse model causes severe seizures. The seizure-causing effect is nearly comparable to that caused by deleting TSC1/2 genes in neurons and astrocytes in rodents. We are excited about this finding. We believe that it points to a novel mechanism of epileptogenesis in TSC and possibly in other forms of epilepsy as well. However, in order to leverage this finding, further work needs to be done. Our study revealed that mice with elevated mTOR activity in microglia develop severe spontaneous recurrent seizures (SRS) without significant induction of pro-inflammatory cytokines. This novel finding indicates there must be an alternative epileptogenic route independent of the inflammatory response. Moreover, our preliminary data revealed that mTOR activation induces robust expression of insulin-like growth factor 1, whereas inhibition of mTOR suppresses expression of IGF1 in microglia. While IGF1 has been known as a potent activator of mTOR, our discovery that mTOR activation in turn up-regulates the expression of IGF in microglia was entirely unexpected. Several questions are raised around this unexpected finding of microglial mTOR/IGF1 axis. Does microglia IGF1 can activate mTOR in the surrounding neurons? Does microglia IGF1 can promote epileptogenesis? We need to accumulate more evidence demonstrating that therapeutics which target the microglia can effectively stop or reduce seizures. This needs to be shown in animal models prior to being translated into the clinical setting. The present proposal is developed closely around these important questions. Results from the proposed studies will not only improve our understanding of epileptogenesis in TSC, but also potentially lead to new treatments for managing epilepsy in TSC. For example, if our hypothesis is correct, we could develop therapeutic strategies to downregulate the mTOR/IGF1 axis activity by depleting microglia or inhibiting IGF1 signaling by small molecules (as we proposed as alternatives in the proposal) so as to alleviate seizure outcomes in TSC patients.