Abstracts

Rationale: Thalamocortical circuits are key for the generation of both partial and generalized epileptic seizures. GABAergic neurons from the reticular thalamic nucleus (nRt) inhibit thalamocortical relay cells (TCR), regulate thalamocortical transmission, and generate cerebral rhythms including those involved in thalamocortical epilepsies. nRt neurons receive excitatory inputs from both corticothalamic and thalamocortical axons and would thus receive strong excitatory input during focal and generalized seizures. The response of nRt neurons to such input is not well understood and could promote reorganization of thalamocortical circuits in ways that may lead to hyperexcitability. We therefore examined possible functional alterations in nRt neurons following prolonged episodes of acute seizure activity in the somatosensory cortex. Methods: Focal status epilepticus (SE) was induced in male P22 mice by unilateral application of a 2 mm pledget of Gelfoam, soaked in 100 ?M GABAzine, to the dura over the somatosensory cortex. Resultant focal electrographic epileptiform activity and associated contralateral partial seizures were monitored for two hours. Mice were then re-anesthetized, the incision reopened, the GABAzine pledget removed and the cortex thoroughly washed with sterile saline. The scalp was then re-sutured and animals allowed to recover. 5-7 days later whole-cell patch-clamp recordings of nRt neurons were obtained from in vitro horizontal brain slices using standard techniques in the presence of inhibitory neurotransmission blockers. Extracellular stimuli delivered to the internal capsule via a concentric bipolar electrode were used to evoke excitatory currents (eEPSCs) in nRt cells, mimicking the excitatory input from the cortex or dorsal thalamus. Results: Two hour episodes of focal SE lead to robust and long-lasting increases in intrinsic excitability and synaptic excitation in nRt neurons. Compared to na ve controls, nRt neurons in post-status animals showed (1) enhanced post-inhibitory rebound of excitation characterized by a 2-fold increased number of rebound action potentials and a 3-fold increased duration of rebound firing; (2) increased amplitude and lowered threshold for EPSCs evoked by minimal stimulation of internal capsular axons. Conclusions: Neocortical focal SE chronically enhances both intrinsic excitability and synaptic excitation of nRt neurons. The resultant powerful increase in inhibitory drive from nRt onto TCR cells might suppress excitatory feedback from thalamus to cortex. However, because the output of nRt neurons controls oscillations in the thalamocortical circuits, the increased GABAergic transmission from nRt to TCR cells following SE might promote abnormal oscillations in thalamocortical circuits, leading to amplification and enhanced propagation of cortical epileptic activity. Future experiments will be required to determine if the SE-induced alterations in nRt translate into enhanced thalamocortical oscillatory and epileptiform activity. Funding: Epilepsy Foundation postdoctoral fellowship and NS06477.