Microglial IGF1 in epileptogenesis

Epileptogenesis is a pathological process that transforms a normal brain into an epileptic brain, typically initiated by genetic mutations and neurological insults such as status epilepticus (SE). Excessive activation of mTOR signaling is recognized as a mechanism underlying both genetic and acquired forms of epilepsy. Modeling hyperactivation of mTOR signaling in neurons and astrocytes recapitulates the epileptogenic activity. However, the role of microglia in epileptogenesis is underexplored. While the inflammatory response of microglia has long been postulated to be epileptogenic, we recently demonstrated 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 (IGF1), 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 was entirely unexpected. These data suggest that the microglial mTOR/IGF1 axis propagates mTOR signaling into other cells in the CNS. Our overarching hypothesis is that elevated mTOR signaling in microglia up-regulates IGF1 expression, which in turn propagates mTOR signaling to the surrounding cells through a paracrine route involving IGF1, consequently disrupting brain homeostasis and resulting in SRS. Three specific aims are proposed to test our hypothesis. Aim 1 will characterize the propagation of microglial IGF1 signaling to non-microglial cells. Aim 2 will evaluate the role of microglial IGF1 in CNS homeostasis. Aim 3 will determine if IGF1 plays a role in epileptogenesis. Our study will not only significantly advance our understanding of how the mTOR signaling mediates epileptogenesis, but could also lead to new strategies to prevent epileptogenesis.