Temporal lobe epilepsy (TLE) is the most prevalent form of partial epilepsy, often refractory to treatment, with limbic structures, including hippocampus, implicated in seizure generation. Once a seizure occurs, there is increased risk for seizure recurrence, and seizures themselves act to further establish aberrant networks. Even though this pattern of post-seizure progression is well studied in animal models of kindling in which an initial period of intense seizures is caused by chemical treatment or physiological induction, little is known about the mechanisms that produce a first seizure episode, especially when epilepsy emerges in the absence of genetic causes or injury. Kindling studies support a role for seizure-induced increases in hippocampal brain-derived neurotrophic factor (BDNF) signaling in the development of subsequent seizures, raising the possibility that normal BDNF functions may be co-opted by seizure activity to reshape synaptic organization. We can extrapolate that persistent disruptions in BDNF regulation per se may similarly reshape organization to favor formation of pro- epileptic circuitry. This application uses a transgenic mouse strain that over-expresses the BDNF in the forebrain under the calcium/calmodulin-dependent kinase II alpha promoter (TgBDNF) as a model to study slow and progressive remodeling of synaptic circuits that marks the transition from normal to epileptic brain without prior kindling. A subset of TgBDNF mice develops spontaneous seizures in response to tail lifting & cage agitation at mid-adulthood with increasing numbers of mice becoming epileptic with age. Increased BDNF is shown to disrupt the normal structural organization of the hippocampal dentate gyrus by modifying the morphology of granule cells (GCs) prior to emergence of seizures. We hypothesize that BDNF chronically drives structural changes in the dentate to gradually disrupt gating function, leading to seizure emergence; and in this sense, its increase may constitute a common epileptogenic thread across some animal models.
In Aim 1 we will document the progression of changes in brain network activity and accompanying behaviors, from young adulthood until convulsive seizures emerge, using combined EEG-video surveillance in TgBDNF model. Anatomical techniques will map the brain structures/circuits that show altered activity over this period.
In Aim 2 we will determine if excess BDNF alone is sufficient to produce aberrant integration of adult-generated GCs on route to convulsive seizures in TgBDNF mice.
In Aim 3, we will test if modest, conditional inhibition of dentate TrkB expression reverses epileptogenesis and restores gating properties of GCs in the TgBDNF model.
Abnormal changes in the activity of forebrain circuits are associated with range of neurological disorders, including epilepsy, with the underlying causes often unknown. Elucidating the mechanisms that drive the transition from normal to seizure prone brain can aid in developing novel intervention strategies. This project uses a brain-derived neurotrophic factor (BDNF) over-expressing mice that develop spontaneous seizures at ~ 6 months of age, providing a sizeable time window to study evolution of epilepsy and emergence of hippocampal aberrant synaptic networks. This project will determine if chronic increases in BDNF drive progressive, detrimental reorganization of forebrain circuitry, leading to hyperexcitability and the gradual emergence of spontaneous, epileptic seizures.
