NR2A-Containing NMDARs in the Prefrontal Cortex Are Required for Working Memory and Associated with Age-Related Cognitive Decline
| Autor: | Charles J. Frazier, Kyle B. Kelly, Kailey L. Simpson, Barry Setlow, Jennifer L. Bizon, Joseph A. McQuail, B. Sofia Beas |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Aging Age-related cognitive decline Patch-Clamp Techniques Prefrontal Cortex Receptors N-Methyl-D-Aspartate 03 medical and health sciences 0302 clinical medicine mental disorders Serine Animals Cognitive Dysfunction Prefrontal cortex Research Articles Memory Disorders Psychiatric Disease Working memory Long-term memory Pyramidal Cells musculoskeletal neural and ocular physiology General Neuroscience Cognition Rats Inbred F344 Rats Memory Short-Term 030104 developmental biology nervous system Conditioning Operant NMDA receptor Psychology Excitatory Amino Acid Antagonists Neuroscience psychological phenomena and processes 030217 neurology & neurosurgery Signal Transduction Neuropsychiatric disease |
| Zdroj: | The Journal of Neuroscience. 36:12537-12548 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.2332-16.2016 |
| Popis: | 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.SIGNIFICANCE STATEMENTWorking 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. |
| Databáze: | OpenAIRE |
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