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BACKGROUND: Multiple Sclerosis (MS) is an autoimmune neurodegenerative disease, whose primary hallmark is the occurrence of inflammatory lesions in white and grey matter structures. Increasing evidence in MS patients and respective murine models reported an impaired ionic homeostasis driven by inflammatory-demyelination, thereby profoundly affecting signal propagation. However, the impact of a focal inflammatory lesion on single-cell and network functionality has hitherto not been fully elucidated. OBJECTIVES: In this study, we sought to determine the consequences of a localized cortical inflammatory lesion on the excitability and firing pattern of thalamic neurons in the auditory system. Moreover, we tested the neuroprotective effect of Retigabine (RTG), a specific Kv7 channel opener, on disease outcome. METHODS: To resemble the human disease, we focally administered pro-inflammatory cytokines, TNF-α and IFN-γ, in the primary auditory cortex (A1) of MOG35-55 immunized mice. Thereafter, we investigated the impact of the induced inflammatory milieu on afferent thalamocortical (TC) neurons, by performing ex vivo recordings. Moreover, we explored the effect of Kv7 channel modulation with RTG on auditory information processing, using in vivo electrophysiological approaches. RESULTS: Our results revealed that a cortical inflammatory lesion profoundly affected the excitability and firing pattern of neighboring TC neurons. Noteworthy, RTG restored control-like values and TC tonotopic mapping. CONCLUSION: Our results suggest that RTG treatment might robustly mitigate inflammation-induced altered excitability and preserve ascending information processing.
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Introduction: Genetic Absence Epilepsy Rats from Strasbourg (GAERS) represent a model of genetic generalized epilepsy. The present longitudinal study in GAERS and age-matched non-epileptic controls (NEC) aimed to characterize the epileptic brain network using two functional measures, resting state-functional magnetic resonance imaging (rs-fMRI) and manganese-enhanced MRI (MEMRI) combined with morphometry, and to investigate potential brain network alterations, following long-term seizure activity. Methods: Repeated rs-fMRI measurements at 9.4 T between 3 and 8 months of age were combined with MEMRI at the final time point of the study. We used graph theory analysis to infer community structure and global and local network parameters from rs-fMRI data and compared them to brain region-wise manganese accumulation patterns and deformation-based morphometry (DBM). Results: Functional connectivity (FC) was generally higher in GAERS when compared to NEC. Global network parameters and community structure were similar in NEC and GAERS, suggesting efficiently functioning networks in both strains. No progressive FC changes were observed in epileptic animals. Network-based statistics (NBS) revealed stronger FC within the cortical community, including regions of association and sensorimotor cortex, and with basal ganglia and limbic regions in GAERS, irrespective of age. Higher manganese accumulation in GAERS than in NEC was observed at 8 months of age, consistent with higher overall rs-FC, particularly in sensorimotor cortex and association cortex regions. Functional measures showed less similarity in subcortical regions. Whole brain volumes of 8 months-old GAERS were higher when compared to age-matched NEC, and DBM revealed increased volumes of several association and sensorimotor cortex regions and of the thalamus. Discussion: rs-fMRI, MEMRI, and volumetric data collectively suggest the significance of cortical networks in GAERS, which correlates with an increased fronto-central connectivity in childhood absence epilepsy (CAE). Our findings also verify involvement of basal ganglia and limbic regions. Epilepsy-related network alterations are already present in juvenile animals. Consequently, this early condition seems to play a greater role in dynamic brain function than chronic absence seizures.
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Cuprizone (CPZ)-induced alterations in axonal myelination are associated with a period of neuronal hyperexcitability and increased activity of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels in the thalamocortical (TC) system. Substances used for the treatment of multiple sclerosis (MS) have been shown to normalize neuronal excitability in CPZ-treated mice. Therefore, we aimed to examine the effects of diroximel fumarate (DRF) and the sphingosine 1-phospate receptor (S1PR) modulator siponimod on action potential firing and the inward current (Ih) carried by HCN ion channels in naive conditions and during different stages of de- and remyelination. Here, DRF application reduced Ih current density in ex vivo patch clamp recordings from TC neurons of the ventrobasal thalamic complex (VB), thereby counteracting the increase of Ih during early remyelination. Siponimod reduced Ih in VB neurons under control conditions but had no effect in neurons of the auditory cortex (AU). Furthermore, siponimod increased and decreased AP firing properties of neurons in VB and AU, respectively. Computational modeling revealed that both DRF and siponimod influenced thalamic bursting during early remyelination by delaying the onset and decreasing the interburst frequency. Thus, substances used in MS treatment normalize excitability in the TC system by influencing AP firing and Ih.