Maintenance and termination of neocortical oscillations by dynamic modulation of intrinsic and synaptic excitability

Abstract

Mechanisms underlying seizure cessation remain elusive. The Lennox-Gastaut syndrome, a severe childhood epileptic disorder, is characterized by episodes of seizure with alternating epochs of spike-wave and fast run discharges. In a detailed computational model that incorporates extracellular potassium dynamics, we studied the dynamics of these state transitions between slow and fast oscillations. We show that dynamic modulation of synaptic transmission can cause termination of paroxysmal activity. An activity-dependent shift in the balance between synaptic excitation and inhibition towards more excitation caused seizure termination by favoring the slow oscillatory state, which permits recovery of baseline extracellular potassium concentration. We found that slow synaptic depression and change in chloride reversal potential can have similar effects on the seizure dynamics. Our results indicate a novel role for synaptic dynamics during epileptic neural activity patterns.

Fig. 1. Cortical network oscillation patterned into alternating epochs of slow bursting and fast run following stimulation of PYs

(A) Top: Activity of all 80 PYs as a function of time. Middle: INs. Bottom: [K⁺]_o time-course. After an initial transient increase, [K⁺]_o increases and decreases during fast run and slow bursting, respectively. (B) Activity of all 80 PYs during slow bursting. (C) Membrane voltage time-course during fast run (top) and slow bursting (bottom). Scale bars: top, 20 msec; bottom, 100 msec.

Fig. 2. Patterned cortical network oscillations of finite length for slow depression of synaptic transmission

(A) Activity of all 80 PYs as a function of time. (B) Time-course of changes in [K⁺]_o. (C) Phase-space representation of normalized synaptic coupling strength. Dynamic change in balance between excitation and inhibition (red line). Arrowhead indicates direction of time. Blue diagonal lines delimit the region for which alternating epochs of fast run and slow bursting can occur infinitely. The box corresponds to the values of synaptic coupling strengths for which we found persistent oscillations in a small network with the same dynamics (Frohlich et al., 2006). (D) Time-course of membrane voltage before termination of oscillations shows slow bursting.

Fig. 3

(A,B) Ten instances of patterned oscillatory firing for slow synaptic depression rate D = 0.001 (A) and D = 0.0011 (B). Black, gray, and white denote slow bursting, fast run and silence, respectively. (C) Phase–space representation of normalized excitation and inhibition (Left, D = 0.001; right, D = 0.0011). Circles, endpoints with termination of oscillations; stars, endpoint with no termination of oscillations within 150 sec. (D) Left, duration of seizures. Right, number of epochs of fast runs. Stars, median values.

Fig. 4. Patterned cortical network oscillations of finite length for dynamically updated intracellular chloride concentration

(A) Activity of all 80 PYs as a function of time. (B) Time-course of changes in intracellular chloride concentration ([Cl⁻]_i). Corresponding reversal potentials are shown for the onset and the end of oscillations. (C) Symbolic phase–space representation of dynamic change in balance between excitation and inhibition (red line). Arrowhead indicates direction of time. Blue diagonal lines delimit the region for which alternating epochs of fast run and slow bursting can occur infinitely. (D) Time-course of membrane voltage before termination of oscillations.

Fig. 5. Spontaneous firing patterns of regular-spiking and fast-spiking cortical neurons during electrographic seizure in vivo

(A) EEG and simultaneous dual intracellular recordings of regular-spiking and fast-spiking neurons (indicated) during seizure that is composed of spike-wave components and fast runs. The seizure evolves from slow oscillation. The fast-spiking inhibitory interneuron is active throughout the seizure. (B,C) Expansions of underlined fragments. (B) Intracellular activities during transition from slow oscillation to seizure. The fast-spiking neuron fires much more spikes than the regular-spiking neuron. (C) During spike-wave complexes the regular-spiking neuron displays one spike, whereas the fast-spiking neuron maintains ability to fire high-frequency trains of spikes.