Modulation of pacemaker channel function in a model of thalamocortical hyperexcitability by demyelination and cytokines

Abstract

A consensus is yet to be reached regarding the exact prevalence of epileptic seizures or epilepsy in multiple sclerosis (MS). In addition, the underlying pathophysiological basis of the reciprocal interaction among neuroinflammation, demyelination, and epilepsy remains unclear. Therefore, a better understanding of cellular and network mechanisms linking these pathologies is needed. Cuprizone-induced general demyelination in rodents is a valuable model for studying MS pathologies. Here, we studied the relationship among epileptic activity, loss of myelin, and pro-inflammatory cytokines by inducing acute, generalized demyelination in a genetic mouse model of human absence epilepsy, C3H/HeJ mice. Both cellular and network mechanisms were studied using in vivo and in vitro electrophysiological techniques. We found that acute, generalized demyelination in C3H/HeJ mice resulted in a lower number of spike–wave discharges, increased cortical theta oscillations, and reduction of slow rhythmic intrathalamic burst activity. In addition, generalized demyelination resulted in a significant reduction in the amplitude of the hyperpolarization-activated inward current (Ih) in thalamic relay cells, which was accompanied by lower surface expression of hyperpolarization-activated, cyclic nucleotide-gated channels, and the phosphorylated form of TRIP8b (pS237-TRIP8b). We suggest that demyelination-related changes in thalamic Ih may be one of the factors defining the prevalence of seizures in MS.

Effects of Axonal Demyelination, Inflammatory Cytokines and Divalent Cation Chelators on Thalamic HCN Channels and Oscillatory Bursting

“…We assessed the influence of axonal demyelination on I h current in TC neurons in a standard laboratory mouse strain. We used a toxic model of acute general demyelination in the CNS by targeting mature oligodendrocytes and feeding mice for 5 weeks with the copper chelator CPZ [ 37 , 40 , 63 ]. Different electrophysiological readouts were obtained on Day1 (full demyelination), Day7 (early remyelination) and Day25 (complete remyelination) after stopping CPZ feeding.…”

“…Here, we assessed the influence of axonal de- and remyelination processes on intrinsic I h current in TC VB neurons by feeding C57BL/6J mice with the copper chelator CPZ for five consecutive weeks [ 37 , 39 , 40 , 42 , 63 ]. While this treatment targets mature oligodendrocytes, we aimed to distinguish this effect from changes depending on direct substance binding to HCN channels and divalent cation chelation.…”

“…While both epileptic C3H/HeJ and non-epileptic C57BL/6J mice display lowered I h currents in TC VB neurons on Day1 and properties like in control mice on Day25, there were diverging results on Day7. CPZ-treated C57BL/6J mice are characterized by increased of HCN channel activity on Day7, while C3H/HeJ mice showed decreased current amplitudes ( Figure 6 ; [ 40 ]). Moreover, CPZ-treated C3H/HeJ mice had slowed HCN channel activation kinetics and more hyperpolarized steady-state activation curves on both Day1 and Day7 [ 40 ].…”

“…In the thalamus, focal demyelination leads to the reduced occurrence of burst firing in TC neurons, indicating an effect on ion channels involved in burst generation [ 38 ]. Indeed, CPZ-induced demyelination of epileptic C3H/HeJ mice resulted in the reduced slow rhythmic intrathalamic burst activity that was associated with a significant reduction of I h in TC cells, lower surface expression of HCN channels, and the reduction in the phosphorylated form of TRIP8b (pS237-TRIP8b) [ 40 ].…”

“…Indeed, it has been shown that IL-1β and IL-6 influence passive and active membrane properties of TC neurons in C57BL/6J mice [ 49 ]. Furthermore, IFN-α and IL-1β differentially modulate I h in TC neurons in epileptic C3H/HeJ mice [ 40 ].…”