Figure 1.

Model of glial-mediated loss of rhythmic activity following retroviral infection. Excitatory input (red spikes, red neuron) to a circuit consisting of recurrently connected rebound neurons (blue neurons) results in an output of periodic oscillating bursts (violet output neuron, violet spikes). Both rebound neurons are inhibitory, forming a recurrent inhibitory circuit that converts a sustained excitatory input to a bursting pattern due to the alternation between inhibition and rebound firing. A) In the uninfected condition, increases in calcium concentrations in the extracellular space, which result from activity in the rebound network, are sequestered by surrounding glia. Glial activation required to begin the process of calcium-sequestration is initiated by NG2 cells through their synaptic connections to rebound neurons, their ability to transduce signals through action potential generation, and their connections to other glial cells. As a result, there is minimal calcium entry into rebound neurons through neuronal calcium leak channels. L-type Ca⁺⁺ channels underlying rebound spiking recover rapidly from calcium-dependent inactivation and the rebound-initiated rhythm is maintained during constant excitatory input. The consequent alternation between inhibition and rebound spiking that result in rhythmic bursting in the output neuron also serves to prevent activation of excitatory conductances in the output neuron that could evoke arrhythmic firing. B) Following infection and subsequent loss of NG2 function, an excitatory input to the rebound network may evoke an initial rebound response (not illustrated). However, calcium concentrations build up in the extracellular space, as a result of which, calcium enters rebound neurons through calcium leak channels. Increased cytoplasmic calcium leads to prolonged inactivation of L-type Ca⁺⁺ channels, with subsequent failure to generate rebound spiking following inhibition. Inhibition within the rebound network is therefore no longer able to convert a sustained excitatory input to a rhythmic output. Consequently, the output neuron responds to the sustained excitation both as a follower neuron and with added intrinsic conductances that prolong firing and can result in hyperexcitability. At early times following glial disruption and subsequent accumulation of calcium ions in the extracellular space, rhythm-generation remains but is abnormal (Output: early). As the accumulation of extracellular calcium increases, calcium entering rebound neurons through calcium leak channels is unable to be buffered sufficiently. Rebound neurons become hyperexcitable and their inhibitory effect on the output neuron is transiently elevated, resulting in loss of spiking and arrhythmic firing (Output: late). The loss of rebound neurons in the network at later times results in the absence of their inhibitory modulation, and the output becomes non-rhythmic and prolonged (Output: very late).