Kcnq3 channels shape active membrane properties and firing signatures of thalamocortical neurons during postnatal development

Background Ascending somatosensory pathways are formed before birth and refined in the early postnatal stages through activity-dependent mechanisms. In this context, the electrophysiological maturation of thalamocortical (TC) neurons is crucial to tune growing circuitry and ensure the fidelity of information processing. Accordingly, perturbations in ionic homeostasis during this vulnerable period might result in neurodevelopmental disorders. Encoded by Kcnq2 and Kcnq3 , Kv7 or M-channels primarily assemble into hetero-tetramers under physiological conditions to mediate a subthreshold potassium current, termed M-current (I M ), that regulates intrinsic excitability and neuronal firing signatures. Yet, how partial or complete absence of Kcnq3 subunits affects active and passive properties of developing TC neurons has hitherto not been fully elucidated. Methods Here, by performing patch-clamp recordings in the mouse ventrobasal thalamic complex (VB), we provide a comprehensive electrophysiological characterization of the I M during postnatal development. We used transgenic mice carrying Kcnq3 mutations, corresponding to human orthologous variants associated with childhood forms of epilepsy, to investigate the impact of Kcnq3 full deletion and haploinsufficiency on the membrane properties and specific firing pattern of TC neurons. Furthermore, we determined the differential contribution of KCNQ2 and KCNQ3 channels to I M generation by expressing the human gene plasmids in Chinese hamster ovary (CHO) cells at defined subunit ratios. Results Pharmacological modulation with the Kcnq opener retigabine (RTG) revealed a gradual increase in I M magnitude during the first 30 postnatal days, whereas relative Kcnq2 and Kcnq3 transcripts remained unchanged across development. In the partial or complete absence of Kcnq3 channels, TC neurons exhibited hyperexcitability, characterized by enhanced burst firing and altered single action potential waveform. In accordance with these findings, equimolar KCNQ2/KCNQ3 expression evoked larger currents compared to either KCNQ2-dominant or KCNQ3-dominant subunit compositions. Conclusion Our results suggest a central role for the Kcnq3 channels in stabilizing the membrane properties and firing mode of developing TC neurons, thus ensuring the faithful transmission of peripheral input to the cerebral cortex.