Ambient Glutamate Promotes Paroxysmal Hyperactivity in Cortical Pyramidal Neurons at Amyloid Plaques via Presynaptic mGluR1 Receptors.
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.
German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Straße 17, 81377 Munich, Germany.|Center for Neuropathology and Prion Research, Ludwig Maximilian University, Feodor-Lynen-Straße 23, 81377 Munich, Germany.
Saak Victor
SV
Ovsepian
German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Straße 17, 81377 Munich, Germany.|Center for Neuropathology and Prion Research, Ludwig Maximilian University, Feodor-Lynen-Straße 23, 81377 Munich, Germany.
Lidia
L
Blazquez-Llorca
German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Straße 17, 81377Munich, Germany.
Susana Valero
SV
Freitag
Center for Neuropathology and Prion Research, Ludwig Maximilian University, Feodor-Lynen-Straße 23, 81377 Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), Ludwig Maximilian University, Feodor-Lynen-Straße 17, 81377 Munich, Germany.
Eva Ferreira
EF
Rodrigues
German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Straße 17, 81377 Munich, Germany.|Center for Neuropathology and Prion Research, Ludwig Maximilian University, Feodor-Lynen-Straße 23, 81377 Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), Ludwig Maximilian University, Feodor-Lynen-Straße 17, 81377 Munich, Germany.
Jochen
J
Herms
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D058225:Plaque, Amyloid / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D017661:Receptors, Presynaptic / Q000187:drug effects; D009435:Synaptic Transmission / Q000502:physiology
D001565:Benzoates; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; D017661:Receptors, Presynaptic; C104077:metabotropic glutamate receptor type 1; C079694:alpha-methyl-4-carboxyphenylglycine; D018698:Glutamic Acid; D005998:Glycine
Alzheimer's disease; ambient glutamate; amyloid plaque; dystrophic axons; mGluR1; prefrontal cortex; synaptic transmission