Ionic mechanisms underlying synchronized oscillations and propagating waves in a model of ferret thalamic slices

Abstract

1. A network model of thalamocortical (TC) and thalamic reticular (RE) neurons was developed based on electrophysiological measurements in ferret thalamic slices. Single-compartment TC and RE cells included voltage- and calcium-sensitive currents described by Hodgkin-Huxley type of kinetics. Synaptic currents were modeled by kinetic models of α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA), γ-aminobutyric acid-A (GABA(A)) and GABA(B) receptors. 2. The model reproduced successfully the characteristics of spindle and slow bicuculline-induced oscillations observed in vitro. The characteristics of these two types of oscillations depended on both the intrinsic properties of TC and RE cells and their pattern of interconnectivity. 3. The oscillations were organized by the reciprocal recruitment between TC and RE cells, due to their mutual connectivity and bursting properties. TC cells elicited AMPA-mediated excitatory postsynaptic potentials (EPSPs) in RE cells, whereas RE cells elicited a mixture of GABA(A) and GABA(B) inhibitory postsynaptic potentials (IPSPs) in TC cells. Because of the presence of a T current, sufficiently strong EPSPs could elicit a burst in RE cells, and TC cells could generate a rebound burst following GABAergic IPSPs. Under these conditions, interaction between the TC and RE cells produced sustained oscillations. 4. In the absence of spontaneous oscillation in any cell, the TC-RE network remained quiescent. Spindle oscillations with a frequency of 9-11 Hz could be initiated by stimulation of either TC or RE neurons. A few spontaneously oscillating TC neurons recruited the entire network model into a 'waxing-and-waning' oscillation. These 'initiator' cells could be an extremely small proportion of TC cells. 5. In intracellular recordings, TC cells display a reduced ability for burst firing after a sequence of bursts. The 'waning' phase of spindles was reproduced in the network model by assuming an activity- dependent upregulation of I(h) operating via a calcium-binding protein in TC cells, as shown previously in a two cell model. 6. Following the global suppression of GABA(A) inhibition, the disinhibited RE cells produced prolonged burst discharges that elicited strong GABA(B)-mediated currents in TC cells. The enhancement of slow IPSPs in TC cells was also due to cooperativity in the activation of GABA(B)-mediated current. These slow IPSPs recruited TC and RE cells into slower waxing-and-waning oscillations (3-4 Hz) that were even more highly synchronized. 7. Local axonal arborization of the TC to RE and RE to TC projections allowed oscillations to propagate through the network. An oscillation starting at a single focus induced a propagating wavefront as more cells were recruited progressively. The waning of the oscillation also propagated due to upregulation of I(h) in TC cells, leading to waves of spindle activity as observed in experiments. 8. The spatiotemporal properties of propagating waves in the model were highly dependent on the intrinsic properties of TC cells. The spatial pattern of spiking activity was markedly different for spindles compared with bicuculline-induced oscillations and depended on the rebound burst behavior of TC cells. The upregulation of I(h) produced a refractory period so that colliding spindle waves merged into a single oscillation and extinguished. Finally, reducing the I(h) conductance led to sustained oscillations. 9. Two key properties of cells in the thalamic network may account for the initiation, propagation, and termination of spindle oscillations, the activity-dependent upregulation of I(h) in TC cells, and the localized axonal projections between TC and RE cells. In addition, the model predicts that a nonlinear stimulus dependency of GABA(B) responses accounts for the genesis of prolonged synchronized discharges following block of GABA(A) receptors.