biostudies-literaturePaul JRNINDS NIH HHS13470https://www.ebi.ac.uk/biostudies/studies/S-EPMC5114562biostudies-literatureUnknown7How neurons encode intracellular biochemical signalling cascades into electrical signals is not fully understood. Neurons in the central circadian clock in mammals provide a model system to investigate electrical encoding of biochemical timing signals. Here, using experimental and modelling approaches, we show how the activation of glycogen synthase kinase 3 (GSK3) contributes to neuronal excitability through regulation of the persistent sodium current (I_NaP). I_NaP exhibits a day/night difference in peak magnitude and is regulated by GSK3. Using mathematical modelling, we predict and confirm that GSK3 activation of I_NaP affects the action potential afterhyperpolarization, which increases the spontaneous firing rate without affecting the resting membrane potential. Together, these results demonstrate a crucial link between the molecular circadian clock and electrical activity, providing examples of kinase regulation of electrical activity and the propagation of intracellular signals in neuronal networks.Nature communicationsRegulation of persistent sodium currents by glycogen synthase kinase 3 encodes daily rhythms of neuronal excitability.PMC5114562R01 NS082413F31 NS086282DeWoskin DForger DBGamble KLMcMeekin LJPaul JRCowell RMfalseRegulation of persistent sodium currents by glycogen synthase kinase 3 encodes daily rhythms of neuronal excitability.How neurons encode intracellular biochemical signalling cascades into electrical signals is not fully understood. Neurons in the central circadian clock in mammals provide a model system to investigate electrical encoding of biochemical timing signals. Here, using experimental and modelling approaches, we show how the activation of glycogen synthase kinase 3 (GSK3) contributes to neuronal excitability through regulation of the persistent sodium current (I_NaP). I_NaP exhibits a day/night difference in peak magnitude and is regulated by GSK3. Using mathematical modelling, we predict and confirm that GSK3 activation of I_NaP affects the action potential afterhyperpolarization, which increases the spontaneous firing rate without affecting the resting membrane potential. Together, these results demonstrate a crucial link between the molecular circadian clock and electrical activity, providing examples of kinase regulation of electrical activity and the propagation of intracellular signals in neuronal networks.2016-01-01T00:00:00Z2016 Nov2025-04-25T19:23:18.96Z2019-03-27T02:29:16ZS-EPMC51145622784135110.1038/ncomms13470