Neurobiology of Disease Enhanced NMDA Receptor-Dependent Thalamic Excitation and Network Oscillations in Stargazer Mice

Disturbances in corticothalamic circuitry can lead to absence epilepsy. The reticular thalamic nucleus (RTN) plays a pivotal role in that it receives excitation from cortex and thalamus and, when strongly activated, can generate excessive inhibitory output and epileptic thalamocortical oscillations thatdependonpostinhibitory rebound. Stargazer (stg)micehaveprominent absence seizures resulting from amutant formof theAMPARauxiliaryprotein stargazin.ReducedAMPARexcitation inRTNhasbeendemonstratedpreviously in stg, yet the mechanisms leading from RTN hypoexcitation to epilepsy are unknown and unexpected because thalamic epileptiform oscillatory activity requires AMPARs.We demonstrate hyperexcitability in stg thalamic slices and further characterize the various excitatory inputs to RTN using electrical stimulation and laser scanning photostimulation. Patch-clamp recordings of spontaneous and evoked EPSCs in RTN neurons demonstrate reduced amplitude and increased duration of the AMPAR component with an increased amplitude NMDAR component. Short 200 Hz stimulus trains evoked a gradual approximately threefold increase in NMDAR EPSCs compared with single stimuli inwild-type (WT), indicatingprogressiveNMDARrecruitment,whereas in stg cells,NMDARresponseswerenearlymaximalwith single stimuli. Array tomography revealed lower synaptic, but higher perisynaptic, AMPAR density in stg RTN. Increasing NMDAR activity via reduced [Mg2]o inWTphenocopied the thalamic hyperexcitability observed in stg, whereas changing [Mg 2]o hadno effect on stg slices. These findings suggest that, in stg, a trafficking defect in synaptic AMPARs in RTN cells leads to a compensatory increase in synaptic NMDARs and enhanced thalamic excitability