Format

Send to

Choose Destination
Aging (Albany NY). 2019 Jul 24;11(14):5140-5157. doi: 10.18632/aging.102108.

Subunit contribution to NMDA receptor hypofunction and redox sensitivity of hippocampal synaptic transmission during aging.

Author information

1
Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL 32611, USA.
2
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32611, USA.
3
Genetics and Genomics Program, University of Florida, Gainesville, FL 32611, USA.

Abstract

We examined the contribution of N-methyl-D-aspartate receptor (NMDAR) subunits in the redox-mediated decline in NMDAR function during aging. GluN2A and GluN2B selective antagonists decreased peak NMDAR currents to a similar extent in young and aged animals, indicating that a shift in diheteromeric GluN2 subunits does not underlie the age-related decrease in the NMDAR synaptic function. Application of dithiothreitol (DTT) in aged animals, increased peak NMDAR synaptic currents, prolonged the decay time, and increased the sensitivity of the synaptic response to the GluN2B antagonist, ifenprodil, indicating that DTT increased the contribution of GluN2B subunits to the synaptic response. The DTT-mediated increase in NMDAR function was inhibited by partial blockade of NMDARs, and this inhibition was rescued by increasing Ca2+ concentration in the recording medium. The results indicate that DTT-mediated potentiation requires Ca2+ influx through NMDAR activity. Finally, redox regulation of NMDAR function depends on the activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII). The results indicate that activity-dependent NMDAR synaptic plasticity is suppressed by redox-mediated inhibition of CaMKII activation during aging. The redox regulation of NMDARs represents a suppression of a metaplasticity mechanism, which can disrupt synaptic plasticity and cognition associated with neurological or psychiatric diseases, and aging.

KEYWORDS:

CA1 pyramidal neurons; NMDA receptor current; aging; dithiothreitol; hippocampus; redox state

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center