Authors :
Presenting Author: Yizhen Zhang, BA – Brown University
Stella Sapantzi, BS – Brown University
Anna Duong, BS – Brown University
Adam Mani, PhD – Brown University
Brian Theyel, MD, PhD – Brown University
Rationale:
Traditionally, the action potential origin in CNS neurons is the axon initial segment. After generation the action potential propagates throughout the cell, with both passive and active components in dendrites and via saltatory conduction along the axon. Evidence from others and our own group also suggests that action potentials can originate from the distal regions of the axons and propagates backwards towards the soma. These are known as ectopic action potentials.
Our group has determined that a large portion (96%) of parvalbumin expressing (PV+) cells in the mouse orbitofrontal cortex fire ectopic action potentials after several hundreds of evoked canonical action potentials. In collaboration with Ethan Goldberg, MD PhD’s group at CHOP, we recently determined that ectopic action potential generation is severely impaired in PV+ cells in a mouse model of Dravet Syndrome. However, little is known about the mechanism, function, pathological relevance, and origin of these ectopic action potentials in the cortex.
Methods:
Here, we present data generated using the whole-cell patch clamp technique in vitro and pharmacological interventions in acutely prepared mouse orbitofrontal cortex slices.
Results:
The data indicate that hyperpolarization-activated cyclic nucleotide-gated channels (HCNCs) and voltage-gated potassium channels mediate and modulate ectopic action potentials in PV+ cells. Tetraethylammonium (TEA) abolished ectopic action potentials in 6/13 PV+ cells, and 4-aminopyridine (4AP) decreased ectopic action potential initiation threshold and increased robustness in all 13 neurons, suggesting a heterogeneous contribution of voltage-gated potassium subtypes to ectopic action potential generation. The hyperpolarization activated cation channel (HCNC) antagonist Ivabradine (30 μM) abolished ectopic action potential generation in 7/10 cells and diminished robustness in all 10 cells. All results are statistically significant (2-tailed T-tests with alpha values of 0.05). While data are still being collected, ZD7288 (30 μM) abolished EAP generation in 7/11 cells, and appeared to enhance EAP generation in 2/11 cells.
Conclusions:
Given prior associations between HCNC deficiencies and some epilepsies, as well as potassium channel abnormalities and epilepsies, our data suggest that ectopic action potential generation in PV+ cells should be investigated as a potential contributor to seizure genesis and propagation.
Funding: NIH Grants K08 NS118114