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: