title: Enhanced NMDA receptor-dependent thalamic excitation and network oscillations in stargazer mice.
abstract: 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 that depend on postinhibitory rebound. Stargazer (stg) mice have prominent absence seizures resulting from a mutant form of the AMPAR auxiliary protein stargazin. Reduced AMPAR excitation in RTN has been demonstrated previously 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 in wild-type (WT), indicating progressive NMDAR recruitment, whereas in stg cells, NMDAR responses were nearly maximal with single stimuli. Array tomography revealed lower synaptic, but higher perisynaptic, AMPAR density in stg RTN. Increasing NMDAR activity via reduced [Mg2+]o in WT phenocopied the thalamic hyperexcitability observed in stg, whereas changing [Mg2+]o had no 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.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Lacey
authors.forename: Astra
authors.initials: A
authors.lastname: Bryant
authors.forename: Julia
authors.initials: J
authors.lastname: Brill
authors.forename: John R
authors.initials: JR
authors.lastname: Huguenard
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000818:Animals; D055592:Biophysical Phenomena / Q000187:drug effects / Q000235:genetics; D015220:Calcium Channels / Q000235:genetics*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004832:Epilepsy, Absence / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005971:Glutamates / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D011810:Quinoxalines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013569:Synapses / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013787:Thalamic Nuclei / Q000473:pathology* / Q000503:physiopathology*; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: C440256:4-methoxy-7-nitroindolinyl-glutamate; C113940:Cacng2 protein, mouse; D015220:Calcium Channels; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D007211:Indoles; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C493465:Slc17a7 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C056639:2-amino-5-phosphopentanoic acid; D014633:Valine