NMDA-mediated Ca(2+) influx drives aberrant ryanodine receptor activation in dendrites of young Alzheimer's disease mice.
Deficits in synaptic function, particularly through NMDA receptors (NMDARs), are linked to late-stage cognitive impairments in Alzheimer's disease (AD). At earlier disease stages, however, there is evidence for altered endoplasmic reticulum (ER) calcium signaling in human cases and in neurons from AD mouse models. Despite the fundamental importance of calcium to synaptic function, neither the extent of ER calcium dysregulation in dendrites nor its interaction with synaptic function in AD pathophysiology is known. Identifying the mechanisms underlying early synaptic calcium dysregulation in AD pathogenesis is likely a key component to understanding, and thereby preventing, the synapse loss and downstream cognitive impairments. Using two-photon calcium imaging, flash photolysis of caged glutamate, and patch-clamp electrophysiology in cortical brain slices, we examined interactions between synaptically and ER-evoked calcium release at glutamatergic synapses in young AD transgenic mice. We found increased ryanodine receptor-evoked calcium signals within dendritic spine heads, dendritic processes, and the soma of pyramidal neurons from 3xTg-AD and TAS/TPM AD mice relative to NonTg controls. In addition, synaptically evoked postsynaptic calcium responses were larger in the AD strains, as were calcium signals generated from NMDAR activation. However, calcium responses triggered by back-propagating action potentials were not different. Concurrent activation of ryanodine receptors (RyRs) with either synaptic or NMDAR stimulation generated a supra-additive calcium response in the AD strains, suggesting an aberrant calcium-induced calcium release (CICR) effect within spines and dendrites. We propose that presenilin-linked disruptions in RyR signaling and subsequent CICR via NMDAR-mediated calcium influx alters synaptic function and serves as an early pathogenic factor in AD.
Goussakov
Ivan
I
Department of Neuroscience, Rosalind Franklin University of Medicine and Science/The Chicago Medical School, North Chicago, Illinois 60064, USA.
Miller
Megan B
MB
Stutzmann
Grace E
GE
D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D019256:Cadmium Chloride / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004195:Disease Models, Animal; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000493:pharmacokinetics*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal / Q000379:methods; D009154:Mutation / Q000235:genetics; D016202:N-Methylaspartate / Q000494:pharmacology*; D018408:Patch-Clamp Techniques / Q000379:methods; D017397:Prefrontal Cortex / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D011503:Transglutaminases; D016875:tau Proteins / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D000697:Central Nervous System Stimulants; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C508853:PSEN1 protein, human; D053764:Presenilin-1; D019837:Ryanodine Receptor Calcium Release Channel; D016875:tau Proteins; D002110:Caffeine; D016202:N-Methylaspartate; D006493:Heparin; D011503:Transglutaminases; C105804:transglutaminase 1; D019256:Cadmium Chloride
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