Glutamate Carboxypeptidase II in Aging Rat Prefrontal Cortex Impairs Working Memory Performance

Abstract

Glutamate carboxypeptidase II (GCPII) expression in brain is increased by inflammation, and reduces NAAG (N-acetyl aspartyl glutamate) stimulation of mGluR3 signaling. Genetic insults in this signaling cascade are increasingly linked to cognitive disorders in humans, where increased GCPII and or decreased NAAG-mGluR3 are associated with impaired prefrontal cortical (PFC) activation and cognitive impairment. As aging is associated with increased inflammation and PFC cognitive deficits, the current study examined GCPII and mGluR3 expression in the aging rat medial PFC, and tested whether GCPII inhibition with 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) would improve working memory performance. We found that GCPII protein was expressed on astrocytes and some microglia as expected from previous studies, but was also prominently expressed on neurons, and showed increased levels with advancing age. Systemic administration of the GCPII inhibitor, 2-MPPA, improved working memory performance in young and aged rats, and also improved performance after local infusion into the medial PFC. As GCPII inhibitors are well-tolerated, they may provide an important new direction for treatment of cognitive disorders associated with aging and/or inflammation.

N-Acetyl-Aspartyl-Glutamate in Brain Health and Disease

“…GCPII is expressed almost exclusively on the plasma membrane of glia, with the catalytic site facing extracellularly. In particular, GCPII is expressed at high levels extracellularly on astrocytes [33] and at lower levels on microglia [34]. GCPIII, on the other hand, localizes more to cerebellar and cortical neurons and less to astrocytes.…”

“…The activation of mGluR3 primarily inhibits presynaptic glutamate release [35], with positive effects on working memory [18,36]. Lower levels of NAAG, leading to the reduced stimulation of mGluR3, are associated with reduced cognitive function [34,37]. Systemic or prefrontal infusion of a GCPII inhibitor, increasing NAAG levels, improved working memory performance in young and aged rats [34] and enhances task-related neuronal firing in monkeys [18].…”

“…Lower levels of NAAG, leading to the reduced stimulation of mGluR3, are associated with reduced cognitive function [34,37]. Systemic or prefrontal infusion of a GCPII inhibitor, increasing NAAG levels, improved working memory performance in young and aged rats [34] and enhances task-related neuronal firing in monkeys [18]. In addition, in humans, increased GCPII expression or gain-of-function mutations in the gene encoding GCPII (Folh1), which leads to decreased NAAG levels, are associated with impaired cognition [31].…”

“…In order to study the effects of increased NAAG or prolonged action of endogenous NAAG, specific inhibitors of GCPII are valuable tools. The phosphonic acid-based GCPII inhibitor 2-(phosphonomethyl) pentanedioic acid (2-PMPA) and the thiol-based inhibitor 2-(3-Mercaptopropyl)pentanedioic acid (2-MPPA) [34] and other inhibitors (Table 1) are instrumental in demonstrating the robust therapeutic effects of GCPII inhibition and NAAG in a number of animal models of disease.…”

Unusual Molecular Regulation of Dorsolateral Prefrontal Cortex Layer III Synapses Increases Vulnerability to Genetic and Environmental Insults in Schizophrenia

“…GCPII expression is increased by inflammation e.g. in the aged rat mPFC (122), and especially relevant to schizophrenia, by perinatal inflammation (123). Thus, inflammation can mimic loss-of-of function mutations in GRM3 by reducing mGluR3 signaling.…”