Abstracts

Rationale: Neocortical rhythmicity plays an extraordinary role in motor coordination, sleep, cognition and attention. However, dysregulation of neocortical rhythmicity may lead to diseases such as pediatric epilepsy, Alzheimer’s disease and Rett Syndrome, as well as, contributing to sleep disruption. Work in several mammalian species suggests the possibility that synchronized oscillations of the neocortex underlying rhythmic sleep and epilepsy are triggered by layer V intrinsic bursting (IB) neurons. However, human IB (hIB) neurons with repetitive bursting properties following synaptic isolation have yet to be described. Although neocortical rhythm generation may theoretically be initiated by IB neurons with voltage-dependent pacemaker properties, rhythmicity has also been proposed to be an emergent property of the neocortical neural network. The latter hypothesis would seem the most plausible, as hIB have not been previously found. Methods: We used current and voltage clamping techniques in human brain slices from neocortex resected from pediatric patients who underwent epilepsy surgery. Synaptic transmission was blocked with either CNQX & CPP or cadmium. Riluzole was used to block the persistent sodium current. Results: Here, we demonstrate that in the human neocortex: 1) layer V, pyramidal IB neurons with voltage-dependent intrinsic, repetitive, bursting properties are present; 2) voltage-dependent intrinsic bursting properties of hIB are not dependent on voltage-gated calcium channels or calcium-mediated synaptic transmission; and 3) hIB neuron bursting properties are blocked by the anti-epileptic, persistent sodium current (INa+(p)) antagonist, riluzole. We also show riluzole application did not alter the fast sodium current underlying action potentials. Conclusions: These data support the hypothesis, that human neocortical rhythmicity may be initiated by IB neurons with voltage-dependent, riluzole-sensitive bursting properties. This finding markedly challenges the suggestion by Benardo (2002) that seizures widely induce intrinsic bursting properties and rhythmicity by increasing hyperexcitability through the enhancement of calcium currents. Supported by NIH RO1 HL079294-02 (AKT) and Parker B. Francis Fellow (AKT) and Falk Family Foundation to CJM & FPE.