Ambient Glutamate Promotes Paroxysmal Hyperactivity in Cortical Pyramidal Neurons at Amyloid Plaques via Presynaptic mGluR1 Receptors
| Autor: | Eva Ferreira Rodrigues, Jochen Herms, Saak V. Ovsepian, Susana Valero Freitag, Lidia Blazquez-Llorca |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
drug effects [Pyramidal Cells] Plaque Amyloid Receptors Metabotropic Glutamate Receptors Presynaptic Synaptic Transmission Benzoates 0302 clinical medicine analogs & derivatives [Glycine] Premovement neuronal activity Axon Neurons Chemistry Pyramidal Cells pharmacology [Excitatory Amino Acid Antagonists] Glutamate receptor physiology [Neurons] medicine.anatomical_structure pharmacology [Glycine] Metabotropic glutamate receptor 1 metabolism [Receptors Metabotropic Glutamate] pharmacology [Benzoates] drug effects [Excitatory Postsynaptic Potentials] metabotropic glutamate receptor type 1 physiology [Excitatory Postsynaptic Potentials] Cognitive Neuroscience drug effects [Receptors Presynaptic] Glycine Glutamic Acid alpha-methyl-4-carboxyphenylglycine Neurotransmission Synaptic vesicle 03 medical and health sciences Cellular and Molecular Neuroscience Glutamatergic medicine Animals drug effects [Neurons] ddc:610 metabolism [Glutamic Acid] Excitatory Postsynaptic Potentials metabolism [Plaque Amyloid] Mice Inbred C57BL 030104 developmental biology Metabotropic receptor nervous system physiology [Synaptic Transmission] Excitatory Amino Acid Antagonists Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Cerebral cortex 27(10), cercor;bhw267v1 (2016). doi:10.1093/cercor/bhw267 |
| ISSN: | 1460-2199 1047-3211 |
| Popis: | Synaptic dysfunctions and altered neuronal activity play major role in the pathophysiology of Alzheimer's disease (AD), with underlying mechanisms largely unknown. We report that in the prefrontal cortex of amyloid precursor protein-presenilin 1 and APP23 AD mice, baseline activity of pyramidal cells is disrupted by episodes of paroxysmal hyperactivity. Induced by spontaneous EPSC bursts, these incidents are prevalent in neurons proximal to amyloid plaques and involve enhanced activity of glutamate with metabotropic effects. Abolition of EPSC bursts by tetrodotoxin and SERCA ATPase blockers thapsigargin or cyclopiasonic acid suggests their presynaptic origin and sensitized store-released calcium. Accordingly, the rate of EPSC bursts activated by single axon stimulation is enhanced. Aggravation of the hyperactivity by blockers of excitatory amino acid transporter (±)-HIP-A and DL-TBOA together with histochemical and ultrastructural evidence for enrichment of plaque-related dystrophies with synaptic vesicles and SNARE protein SNAP-25 infer the later as hot-spots for ectopic release of glutamate. Inhibition of EPSC bursts by I/II mGluR1 blocker MCPG or selective mGluR1 antagonist LY367385 implicate metabotropic glutamatergic effects in generation of paroxysmal bursts. These findings demonstrate for the first time that at amyloid plaques, enhanced activity of nonsynaptic glutamate can promote irregular EPSC bursts with hyperactivity of pyramidal cells via mGluR1 receptors. |
| Databáze: | OpenAIRE |
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