Abstracts

Rationale: The neurotrophin, brain derived neurotrophic factor (BDNF), plays a critical role in neural development, migration, plasticity, recovery from injury and learning. In epileptogenic brain areas, such as the neocortex, BDNF is up-regulated during repeated seizures, whereby it is proposed to enhance glutamatergic synaptic transmission and decrease GABAergic inhibition, enhancing the overall excitability of the network. BDNF is additionally suggested to enhance intrinsic neuronal membrane excitability. Thus, BDNF has been proposed to promote epileptiform activity. Although, BDNF over-expression and exogenous application lead to reduced seizure threshold in experimental models where inhibition is reduced, no one has before shown that BDNF alone induces cortical epileptiform activity. Here, we test the hypothesis that BDNF application can trigger epileptiform activity and enhance neocortical rhythmicity. Methods: We used neocortical brain slice preparations containing temporal lobe cortex of CD-1 mice (age P10-P15), and human brain slices from neocortex resected from patients who underwent epilepsy surgery. We simultaneously recorded network population activity and from individual cortical neurons using whole cell current clamp techniques. Results: In mice, BDNF application (50ng/mL) triggered paroxysmal depolarization shift (PDS) bursting, a hallmark of epileptiform activity; PDS bursts were NMDA-dependent and blocked by the NMDA antagonist, CPP. BDNF enhanced bursting properties in intrinsic bursting (IB) neurons, but not in non-rhythmogenic neurons. Application of BDNF also induced seizure-like population activity in some preparations. In, human neocortex, BDNF also enhanced bursting in human intrinsic bursting neurons. Conclusions: 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. Thus, BDNF signaling may be epileptigenic. Supported by NIH RO1 HL079294-02 (AKT) and Parker B. Francis Fellow (AKT)