Functional relationships between ion channels and intrathalamic rhythmicity: Transgenic animals and pharmacology.

摘要

The connections between thalamus and cortex are responsible for carrying sensory information, and sustaining the rhythmic activity associated with both sleep and absence epilepsy. With the strong association between synchronous cortical activity and thalamic circuits, factors of intrathalamic rhythmicity could become targets for future anti-absence therapies. In this thesis we use whole cell intracellular and multi-unit extracellular recordings from thalamic slices to examine three factors of intrathalamic rhythmicity: T-type Ca2+ channels, the Kv3.1 subunit of voltage activated K + channels, and the δ subunit of GABA_A receptors. First, the central role of T-channels in intrathalamic rhythmicity was suggested by the finding that succinimide anti-absence drugs act as incomplete and non-specific T-channel antagonists. We tested whether the T-channel antagonist U-92032 could provide stronger support for this role. U-92032 specifically suppressed Ca2+-dependent rebound bursts in relay cells, and abolished evoked, slow oscillations in thalamic slices with a similar dose dependence and time course. Second, high-voltage activated K+ channels assembled from the Kv3.1 subunit, display biophysical properties that may contribute to the fast spiking (FS) phenotype. We tested if the FS phenotype of thalamic reticular cells, essential for the high-frequency bursting supporting intrathalamic oscillations, is due to the presence of Kv3.1. After the loss of Kv3.1 there were no substantial changes in single action potential waveforms, or tonic and phasic firing rates, suggesting genetic redundancy in the FS RTN system. Finally, the δ subunit of the heteromultimeric GABA _A receptor is heavily expressed in thalamic relay nuclei and has been shown to slow the desensitization rate and increase GABA affinity in recombinant receptors. We tested whether the GABA_A-mediated synaptic inhibition between reticular and relay cells, which is required for intrathalamic rhythmicity, would be affected by loss of the δ subunit. Although there was a significant change in neurosteroid modulation, we observed only a minor change in the late decay of spontaneous and evoked inhibitory GABA currents. This suggests δ-containing GABA_A receptors may be functionally limited to an extrasynaptic locus in relay cells. The findings presented here add to our knowledge of three molecular components of intrathalamic rhythmicity with potentially modifying roles in absence epilepsy.