NR2A-Containing NMDARs in the Prefrontal Cortex Are Required for Working Memory and Associated with Age-Related Cognitive Decline.
Working memory, the ability to temporarily maintain representational knowledge, is a foundational cognitive process that can become compromised in aging and neuropsychiatric disease. NMDA receptor (NMDAR) activation in prefrontal cortex (PFC) is necessary for the pyramidal neuron activity believed to enable working memory; however, the distinct biophysical properties and localization of NMDARs containing NR2A and NR2B subunits suggest unique roles for NMDAR subtypes in PFC neural activity and working memory. Experiments herein show that working memory depends on NR2A- but not NR2B-NMDARs in PFC of rats and that NR2A-NMDARs mediate the majority of evoked NMDAR currents on layer 2/3 PFC pyramidal neurons. Moreover, attenuated expression of the NR2A but not the NR2B subunit in PFC associates with naturally occurring working memory impairment in aged rats. Finally, NMDAR currents and working memory are enhanced in aged rats by promoting activation of the NR2A-enriched synaptic pool of PFC NMDARs. These results implicate NR2A-NMDARs in normal working memory and suggest novel treatment strategies for improving working memory in cognitive disorders.



Working memory, the ability to hold information "in mind," requires persistent activity of pyramidal neurons in prefrontal cortex (PFC) mediated by NMDA receptor (NMDAR) activation. NMDAR loss in PFC may account for working memory impairments in aging and psychiatric disease. Our studies demonstrate that NMDARs containing the NR2A subunit, but not the NR2B subunit, are required for working memory and that loss of NR2A predicts severity of age-related working memory impairment. The importance of NR2A to working memory is likely due its abundant contribution to pyramidal neuron activity and location at synaptic sites in PFC. This information is useful in designing new therapies to treat working memory impairments by enhancing the function of NR2A-containing NMDARs.
Department of Neuroscience, College of Medicine.
Joseph A
JA
McQuail
Department of Neuroscience, College of Medicine.
B Sofia
BS
Beas
Department of Pharmacodynamics, College of Pharmacy.
Kyle B
KB
Kelly
Department of Neuroscience, College of Medicine.
Kailey L
KL
Simpson
Department of Pharmacodynamics, College of Pharmacy.|McKnight Brain Institute, University of Florida, Gainesville, Florida 32610.
Charles J
CJ
Frazier
Department of Neuroscience, College of Medicine.|Department of Psychiatry, College of Medicine, and.|McKnight Brain Institute, University of Florida, Gainesville, Florida 32610.
Barry
B
Setlow
Department of Neuroscience, College of Medicine, bizonj@ufl.edu.|Department of Psychiatry, College of Medicine, and.|McKnight Brain Institute, University of Florida, Gainesville, Florida 32610.
Jennifer L
JL
Bizon
D000375:Aging / Q000523:psychology*; D000818:Animals; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000523:psychology*; D003216:Conditioning, Operant; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000523:psychology; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; C121001:NR2B NMDA receptor
NMDA receptor; aging; cognition; prefrontal cortex; rat; working memory