Switches in brain states, synaptic plasticity and neuromodulation are fundamental processes in our brain that take place concomitantly across several spatial and timescales. All these processes target neuron intrinsic properties and connectivity to achieve specific physiological goals, raising the question of how they can operate without interfering with each other. Here, we highlight the central importance of a timescale separation in the activation of sodium and T-type calcium channels to sustain robust switches in brain states in thalamic neurons that are compatible with synaptic plasticity and neuromodulation. We quantify the role of this timescale separation by comparing the robustness of rhythms of six published conductance-based models at the cellular, circuit and network levels. We show that robust rhythm generation requires a T-type calcium channel activation whose kinetics are situated between sodium channel activation and T-type calcium channel inactivation in all models despite their quantitative differences.

Background Myotonia congenita (MC) is a common channelopathy affecting skeletal muscle and which is due to pathogenic variants within the CLCN1 gene. Various alterations in the function of the channel have been reported and we here illustrate a novel one. Methods A patient presenting the symptoms of myotonia congenita was shown to bear a new heterozygous missense variant in exon 9 of the CLCN1 gene (c.1010 T > G, p.(Phe337Cys)). Confocal imaging and patch clamp recordings of transiently transfected HEK293 cells were used to functionally analyze the effect of this variant on channel properties. Results Confocal imaging showed that the F337C mutant incorporated as well as the WT channel into the plasma membrane. However, in patch clamp, we observed a smaller conductance for F337C at −80 mV. We also found a marked reduction of the fast gating component in the mutant channels, as well as an overall reduced voltage dependence. Conclusion To our knowledge, this is the first report of a mixed alteration in the biophysical properties of hClC‐1 consisting of a reduced conductance at resting potential and an almost abolished voltage dependence.

Brain function relies on the ability to quickly process incoming information while being capable of forming memories of past relevant events through the formation of novel synaptic connections. Synaptic connections are functionally strengthened or weakened to form new memories through synaptic plasticity rules that strongly rely on neuronal rhythmic activities. Brain information processing, on the other hand, is shaped by fluctuations in these neuronal rhythmic activities, each defining distinctive brain states, which poses the question of how such fluctuations in brain states affect the outcome of memory formation. This question is particularly relevant in the context of sleep-dependent memory consolidation, wakefulness to sleep transitions being characterized by large modifications in global neuronal activity. By combining computational models of neuronal activity switches and plasticity rules, we show that switches to rhythmic brain activity reminiscent of sleep lead to a reset in synaptic weights towards a basal value. This reset is shown to occur both in phenomenological and biophysical models of synaptic plasticity, and to be robust to neuronal and synaptic variability and network heterogeneity. Analytical analyses further show that the mechanisms of the synaptic reset are rooted in the endogenous nature of the sleep-like rhythmic activity. This sleep-dependent reset in synaptic weights permits regularizing synaptic connections during sleep, which could be a key component of sleep homeostasis and has the potential to play a central role in sleep-dependent memory consolidation.

Switches in brain states, synaptic plasticity and neuromodulation are fundamental processes in our brain that take place concomitantly across several spatial and timescales. All these processes target neuron intrinsic properties and connectivity to achieve specific physiological goals, raising the question of how they can operate without interfering with each other. Here, we highlight the central importance of a timescale separation in the activation of sodium and T-type calcium channels to sustain robust switches in brain states in thalamic neurons that are compatible with synaptic plasticity and neuromodulation. We quantify the role of this timescale separation by comparing the robustness of rhythms of six published conductance-based models at the cellular, circuit and network levels. We show that robust rhythm generation requires a T-type calcium channel activation whose kinetics are situated between sodium channel activation and T-type calcium channel inactivation in all models despite their quantitative differences.

We describe a patient presenting the symptoms of myotonia congenita with a new heterozygous missense variant in exon 9 of the CLCN1 gene (c.1010T>G, p.(Phe337Cys)). The mutation is located in the large extracellular loop between the I and J transmembrane segments of CLCN1 and we functionally analyzed its consequences on channel properties. Confocal imaging showed that the F337C mutant incorporated as well as the WT channel into the plasma membrane. Using patch clamp recordings of WT and F337C hClC-1 channels expressed in HEK293 cells, we observed a smaller conductance for the latter at -80 mV. Using classical voltage protocols and curve fitting procedures, we also found a marked reduction of the fast gating component in the mutant channels, as well as an overall reduced voltage-dependence. The mutation did not alter the pharmacology of the channels. Thus the loss of function is due to a reduction of the opening at resting potential and an inability to quickly activate during the action potential and protect the myocytes against repetitive discharges. To our knowledge, this is the first report of a mixed alteration in the biophysical properties of hClC-1 consisting of a reduced conductance at resting potential and an almost abolished voltage dependence.A novel variant in the CLCN1 gene associated with dominant myotonia congenita reduces the macroscopic chloride conductance and strongly dampens its voltage dependence