C06 The role of adult-born granule cells in epileptogenesis

Epileptogenesis is a complex transformative process that converts a normally functioning brain into a brain with repeated seizures.  It is often triggered by a “precipitating insult” such as traumatic brain injury, stroke, inflammation, status epilepticus (SE), brain surgery, tumors, or any physical or chemical trauma sustained by the brain.  The resulting temporal lobe epilepsy (TLE) is drug resistant.  Few mechanistic insights exist into epileptogenesis, let alone any rational pharmacolo­­gical approaches to its prevention.  We will address a major gap in our knowledge about epileptogenesis at cellular and circuit levels following SE in adult mice.  Our preliminary studies have identified specific neurons and circuits critical for the post-SE development of pathological high-frequency oscillations (pHFOs), considered to be harbingers of epileptogenesis.  Our hypothesis is that the most crucial cellular and network contribu­tors to pHFOs and epileptogene­sis after SE are a group of adult born (newly generated) granule cells (abGCs) of the dentate gyrus “struck” by the insult at their most hyperplastic stage of development (i.e., when the abGCs are entering their third week of growth).  At this stage the precipitating insult will “derail” abGCs from their normal cellular maturation and circuit integration, resulting in abnormal connectivity, aberrant firing and synaptic properties which collectively promote pHFOs and epileptogenesis.  We will carry out a comprehensive portrayal of these neurons and their networks that we postulate to be critical for pHFOs and epileptogenesis including the functional characteri­zation using optogenetics, high-resolution in vitro and in vivo recordings, and in vivo single fiber photometric Ca2+-imaging.  We will also address a potential cause for the SE-induced developmental derailment of abGCs: the excessive activation of their NMDA receptors targeted by mossy cells, the neurons most vulnerable to many TLE precipitating insults. Ideally, our experiments will identify critical cellular and network elements during epileptogenesis.  The information can be used to assess and develop novel cell- and circuit-based pharmacological or gene therapy tools aimed at preventing the progression to chronic epilepsy after brain insults.