Attenuated NMDAR signaling on fast-spiking interneurons in prefrontal cortex contributes to age-related decline of cognitive flexibility

Neuropharmacology. 2021 Oct 1;197:108720. doi: 10.1016/j.neuropharm.2021.108720. Epub 2021 Jul 15.


Ionotropic glutamate receptors of the NMDA and AMPA subtypes transduce excitatory signaling on neurons in the prefrontal cortex (PFC) in support of cognitive flexibility. Cognitive flexibility is reliably observed to decline at advanced ages, coinciding with changes in PFC glutamate receptor expression and neuronal physiology. However, the relationship between age-related impairment of cognitive flexibility and changes to excitatory signaling on distinct classes of PFC neurons is not known. In this study, one cohort of young adult (4 months) and aged (20 months) male F344 rats were characterized for cognitive flexibility on an operant set-shifting task. Expression of the essential NMDAR subunit, NR1, was correlated with individual differences in set-shifting abilities such that lower NR1 in the aged PFC was associated with worse set-shifting. In contrast, lower expression of two AMPAR subunits, GluR1 and GluR2, was not associated with set-shift abilities in aging. As NMDARs are expressed by both pyramidal cells and fast-spiking interneurons (FSI) in PFC, whole-cell patch clamp recordings were performed in a second cohort of age-matched rats to compare age-associated changes on these neuronal subtypes. Evoked excitatory postsynaptic currents were generated using a bipolar stimulator while AMPAR vs. NMDAR-mediated components were isolated using pharmacological tools. The results revealed a clear increase in AMPA/NMDA ratio in FSIs that was not present in pyramidal neurons. Together, these data indicate that loss of NMDARs on interneurons in PFC contributes to age-related impairment of cognitive flexibility.

Keywords: AMPA Receptor; Cognition; Interneuron; NMDA Receptor; Normal aging; Prefrontal cortex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / physiology*
  • Animals
  • Cognitive Aging / physiology*
  • Conditioning, Operant
  • Excitatory Postsynaptic Potentials / physiology
  • Interneurons / physiology*
  • Male
  • Patch-Clamp Techniques
  • Prefrontal Cortex / growth & development*
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / physiology*
  • Psychomotor Performance / physiology
  • Pyramidal Cells / physiology
  • Rats
  • Rats, Inbred F344
  • Receptors, AMPA / genetics
  • Receptors, AMPA / physiology
  • Receptors, N-Methyl-D-Aspartate / biosynthesis
  • Receptors, N-Methyl-D-Aspartate / physiology*


  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • glutamate receptor ionotropic, AMPA 2
  • glutamate receptor ionotropic, AMPA 1