Abstract
Glutamate signaling is essential for the persistent neural activity in prefrontal cortex (PFC) that enables working memory. Metabotropic glutamate receptors (mGluRs) are a diverse class of proteins that modulate excitatory neurotransmission via both presynaptic regulation of extracellular glutamate levels and postsynaptic modulation of ion channels on dendritic spines. This receptor class is of significant therapeutic interest for treatment of cognitive disorders associated with glutamate dysregulation. Working memory impairment and cortical hypoexcitability are both associated with advanced aging. Whether aging modifies PFC mGluR expression, and the extent to which any such alterations are regionally or subtype specific, however, is unknown. Moreover, it is unclear whether specific mGluRs in PFC are critical for working memory, and thus, whether altered mGluR expression in aging or disease is sufficient to play a causative role in working memory decline. Experiments in the current study first evaluated the effects of age on medial PFC (mPFC) mGluR expression using biochemical and molecular approaches in rats. Of the eight mGluRs examined, only mGluR5, mGluR3, and mGluR4 were significantly reduced in the aged PFC. The reductions in mGluR3 and mGluR5 (but not mGluR4) were observed in both mRNA and protein, and were selectively localized to the prelimbic (PrL), but not infralimbic (IL), subregion of PFC. Finally, pharmacological blockade of mGluR5 or mGluR2/3 using selective antagonists directed to PrL significantly impaired working memory without influencing non-mnemonic aspects of task performance. Together, these data implicate attenuated expression of PFC mGluR5 and mGluR3 in the impaired working memory associated with advanced ages.
Significance Statement Working memory is impaired in several neuropsychiatric disorders and advanced aging. Glutamate is essential for persistent cellular activity in the prefrontal cortex (PFC) theorized to maintain working memory. Metabotropic glutamate receptors (mGluRs) are well-positioned to coordinate glutamate signaling at PFC synapses; however, studies to date have not yet systematically investigated the contributions of mGluR subtypes to normal working memory and PFC aging. This study shows that aging is accompanied by loss of PFC mGluR2/3 and mGluR5 mRNA and protein, and that pharmacological inhibition of these mGluR subtypes is sufficient to impair working memory. These findings suggest that mGluRs have a normal role in working memory and could serve as a target for treatment of cognitive disorders characterized by PFC dysfunction.
Footnotes
Authors declare no conflict of interes.
Supported by R01AG029421 and the McKnight Brain Research Foundation (JLB), a McKnight Predoctoral Fellowship and the Pat Tillman Foundation (CMH), F32AG051371 (JAM), and a University of Florida University Scholars Program Award (MRS)
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Jump to comment: