Enhanced NMDA Receptor-Dependent Thalamic Excitation and Network Oscillations in Stargazer Mice
Autor: | Julia Brill, Carolyn J. Lacey, Astra S. Bryant, John R. Huguenard |
---|---|
Rok vydání: | 2012 |
Předmět: |
Male
Indoles Patch-Clamp Techniques Time Factors genetic structures Thalamus Action Potentials AMPA receptor In Vitro Techniques Biology Inhibitory postsynaptic potential Receptors N-Methyl-D-Aspartate Article Biophysical Phenomena Statistics Nonparametric Photostimulation Mice Glutamates Quinoxalines Animals Neurons musculoskeletal neural and ocular physiology General Neuroscience Glutamate receptor Excitatory Postsynaptic Potentials Valine biology.organism_classification Electric Stimulation Mice Mutant Strains Disease Models Animal Epilepsy Absence Gene Expression Regulation nervous system Thalamic Nuclei Synapses Vesicular Glutamate Transport Protein 1 Excitatory postsynaptic potential NMDA receptor Female Calcium Channels Nerve Net Excitatory Amino Acid Antagonists Neuroscience Stargazer |
Zdroj: | The Journal of Neuroscience. 32:11067-11081 |
ISSN: | 1529-2401 0270-6474 |
DOI: | 10.1523/jneurosci.5604-11.2012 |
Popis: | 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+]oin WT phenocopied the thalamic hyperexcitability observed in stg, whereas changing [Mg2+]ohad 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. |
Databáze: | OpenAIRE |
Externí odkaz: |