Abstract
19th biennial IPEG Meeting: Nijmegen, The Netherlands. 26-30 October 2016. Background: The family of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels consisiting four different isoforms (HCN1-4) have a major role in controlling neuronal excitability and generation of rhythmic oscillatory activity in individual neurons and neuronal networks. These channels activate in response to hyperpolarizing potentials negative to -50 to -60 mV and depolarize the resting membrane potential. HCN channels are regulated by small molecules like cyclic nucleotides and different accessory proteins. TRIP8b is a brain-specific accessory subunit of HCN channels which controls the gating, surface expression and trafficking of different HCN channels subunits in many regions of brain. The role of this protein for Ih characteristics in thalamic and cortical neurons and the functional consequences of TRIP8b dysregulation for thalamocortical oscillations however is not yet fully understood. The present study aimed at providing a better understanding of the functional role of TRIP8b in the thalamocortical system and shedding some light on possible dysfunctional aspects by combining in vitro and in vivo electrophysiological approaches. In this study, Ih was measured in whole cell patch clamp recordings from thalamocortical (TC) neurons of different thalamic nuclei, as well as pyramidal neurons in layer V and VI of the somatosensory cortex of TRIP8b-deficient (TRIP8b-/-) and control (C57Bl/6 J) mice (p15 - p90). Effects of TRIP8b-dependent dysregulation of Ih on thalamocortical oscillations was monitored by local field potential (LFP) recordings from the ventral-posterior medial complex of the thalamus (VPM) and somatosensory cortex (p 90 - p120), regions which are known to be involved in generation of normal and also pathological thalamocortical oscillations. Results: Characterization of Ih in the thalamocortical system in the absence of the auxiliary subunit TRIP8b showed a significant decrease in Ih density and changes in intrinsic properties and firing patterns of TC and cortical pyramidal neurons. These changes were accompanied by an increase in cAMP sensitivity in TC neurons. Dysregulation of Ih in the thalamocortical system of TRIP8b-/- mice was associated with altered thalamocortical oscillations revealing a significant increase in slow oscillations in the delta frequency range (0.5-4 Hz) during episodes of active-wakefulness. Conclusion: The results of our study point to the importance of TRIP8b, as a brain-specific auxiliary subunit of HCN channels, in regulation of cell and network oscillations. It was demonstrated here that the presence of TRIP8b is necessary for modulation of thalamocortical delta oscillations due to its direct effect on HCN channels protein expression in the thalamocortical system.
