Abstracts

Rationale: The neurotrophin, brain derived neurotrophic factor (BDNF), plays a critical role in neural development, migration, plasticity, recovery from brain injury and learning. In epileptogenic brain areas, such as the neocortex (ctx) and hippocampus (hpp), BDNF is up-regulated during repeated seizures, where it enhances glutamatergic synaptic transmission and decreases GABAergic inhibition, enhancing the overall excitability of the network. BDNF signaling is necessary for seizure induction in experimental models and we found BDNF is sufficient to induce in vitro cortical epileptiform activity and enhance hippocampal rhythmicity. Methods: We used ctx and hpp brain slice preparations of CD-1 mice (age P10-P15) and human brain slices from ctx resected from pediatric patients who underwent epilepsy surgery. We simultaneously recorded network population activity and from individual ctx and hpp neurons using whole cell current clamp techniques. In mice ctx., BDNF induced seizure-like population activity and triggered paroxysmal depolarization shift (PDS) bursting, a hallmark of epileptiform activity. Results: We found BDNF enhances intrinsic neuronal membrane excitability of neocortical intrinsic bursting (IB) neurons, proposed to initiate seizures. PDS bursts were NMDA-dependent and blocked by the NMDA antagonist, CPP. BDNF enhanced bursting properties in IB neurons, but not in non-rhythmogenic neurons. In human ctx, BDNF also enhanced bursting in human IB neurons. In mouse hpp, BDNF enhanced bursting properties in IB neurons. Our data support our working hypothesis that BDNF can preferentially enhance bursting properties of rhythmogenic neurons that may trigger seizure-like activity. Additionally, BDNF can trigger PDS bursting, one of the hallmarks of epilepsy. Conclusions: Our results suggest that BDNF signaling may be involved in epileptogenesis and promotes rhythmicity in cortical and hippocampal networks. Supported by Advancing Healthier Wisconsin Grant (AKT) and Emory T. Clark Foundation (CJM and AKT)