Seizures as imbalanced up states: excitatory and inhibitory conductances during seizure-like events

Abstract

Precisely timed and dynamically balanced excitatory (E) and inhibitory (I) conductances underlie the basis of neural network activity. Normal E/I balance is often shifted in epilepsy, resulting in neuronal network hyperexcitability and recurrent seizures. However, dynamics of the actual excitatory and inhibitory synaptic conductances ( ge and gi, respectively) during seizures remain unknown. To study the dynamics of E and I network balance, we calculated ge and gi during the initiation, body, and termination of seizure-like events (SLEs) in the rat hippocampus in vitro. Repetitive emergent SLEs in 4-aminopyridine (100 μM) and reduced extracellular magnesium (0.6 mM) were recorded in the identified CA1 pyramidal cells (PC) and oriens-lacunosum moleculare (O-LM) interneurons. Calculated ge/ gi ratio dynamics showed that the initiation stage of the SLEs was dominated by inhibition in the PCs and was more balanced in the O-LM cells. During the body of the SLEs, the balance shifted toward excitation, with ge and gi peaking in both cell types at nearly the same time. In the termination phase, PCs were again dominated by inhibition, whereas O-LM cells experienced persistent excitatory synaptic barrage. In this way, increased excitability of interneurons may play roles in both seizure initiation (Žiburkus J, Cressman JR, Barreto E, Schiff SJ. J Neurophysiol 95: 3948–3954, 2006) and in their termination. Overall, SLE stages can be characterized in PC and O-LM cells by dynamically distinct changes in the balance of ge and gi, where a temporal sequence of imbalance shifts with the changing firing patterns of the cellular subtypes comprising the hyperexcitable microcircuits.