Abstract
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.