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

Dibyadeep Datta,Amy F T Arnsten,Miguel Lepe,Shannon N Leslie,Nishita Amancharla,Ayah Elmansy,Elizabeth Woo,Angus C Nairn,Adam P Mecca,Barbara S Slusher

doi:10.3389/fnagi.2021.760270

Dibyadeep Datta, Amy F T Arnsten + Show 8 more

Open Access

https://doi.org/10.3389/fnagi.2021.760270

Copy DOI

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.

Highlights

The enzyme glutamate carboxypeptidase II (GCPII, encoded by the FOLH1 gene) is of growing interest to neuroscientists, as increased Glutamate carboxypeptidase II (GCPII) expression is associated with impaired cognitive function in humans (Zink et al, 2020)
There is renewed interest in the GCPII-NAAG-mGluR3 signaling cascade given the strong relationship between this pathway and cognitive deficits in humans
The current study aimed to analyze the role of GCPII in the aging rat mPFC, a model frequently used to assess molecular mechanisms related to cognitive disorders

Summary

Introduction

The enzyme glutamate carboxypeptidase II (GCPII, encoded by the FOLH1 gene) is of growing interest to neuroscientists, as increased GCPII expression is associated with impaired cognitive function in humans (Zink et al, 2020). Human subjects carrying a gain-of-function mutation in the FOLH1 gene express higher levels of GCPII resulting in decreased levels of NAAG in the brain, as well as inefficient activation of the dorsolateral prefrontal cortex (dlPFC) during working memory, and lower IQ (Zink et al, 2020). As GCPII expression is increased by inflammation (Neale et al, 2005; Cao et al, 2015, 2016; Zhang Z. et al, 2016), and during drug withdrawal (Hicks et al, 2017), GCPII inhibition has therapeutic potential for a range of cognitive disorders associated with inflammatory and dysregulated etiologies

Methods

Results

Conclusion