Abstract #110: Ephaptic coupling, a mechanism for spontaneous neural propagation in the brain

Abstract

It is well documented that synapses play a significant role in the transmission of information between neurons in the brain. However, in the absence of synaptic transmission, neural activity has been observed to continue to propagate. Several experimental results have shown that propagation of epileptiform activity in rodent hippocampi propagates at a speed of ∼0.1 m/s. This observed activity in the 4-AP model propagates independently of synaptic transmission and gap junctions, and is outside the range of ionic diffusion and axonal conduction speeds. Compartment modeling of pyramidal neurons indicate that ephaptic coupling, or endogenous electric fields, could be responsible for this propagation of neural activity in pathological conditions such as epilepsy. Recent studies suggest electric fields can activate neighboring neurons, thereby generating a self-propagating wave. However, there is no experimental data suggesting ephaptic coupling is necessary and sufficient for spontaneous, self-regenerating propagation of neural activity. Using in vitro and in vivo electrophysiology in combination with imaging of trans-membrane voltages using genetically encoded voltage indicators, we test the hypothesis that ephaptic coupling is a critical mechanism for non-synaptic neural propagation. We have developed a novel extracellular electric field clamp capable of measuring the endogenous field and generate an "anti" field to block non-synaptic spontaneous propagation in the rodent hippocampus (Figure 1A). By blocking propagation, we are able to show that ephaptic coupling is a necessary mechanism for propagation of spontaneous activity. Finally, since electric fields propagate as volume conductors, we test if activity can propagate through a complete physical cut of the tissue, thereby eliminating all other forms of close cell-to-cell communication and showing that electric fields alone are sufficient to mediate non-synaptic propagation. Preliminary results suggest that spontaneous epileptiform activity propagates by triggering the activity on the other side across the cut with ephaptic coupling without changing the speed (Figure 1B). Our findings suggest that ephaptic coupling is necessary and sufficient to mediate non-synaptic neural propagation. Further investigation of this mechanism could explain how focal seizures appear to start abruptly and unpredictably, and how the rare micro-seizures of human partial epilepsy (seizure-like events that are not clinically detectable and are resistant to most common antiepileptic drugs) propagate through the hippocampus and cortex. Furthermore, endogenous electric fields could play an important role in brain function and could provide an explanation for unresolved mechanisms of deep brain stimulation or transcranial direct current stimulation (tDCS).