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

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Glutamate carboxypeptidase II (GCPII) expression increases with inflammation, reducing N-acetyl aspartyl glutamate (NAAG) stimulation of mGluR3 signaling.
• Genetic factors affecting the NAAG-mGluR3 pathway are linked to human cognitive disorders, with elevated GCPII or reduced NAAG-mGluR3 associated with impaired prefrontal cortex (PFC) function.
• Aging involves increased inflammation and PFC cognitive deficits, necessitating investigation into GCPII and mGluR3 roles in cognitive aging.

Purpose of the Study:

• To investigate GCPII and mGluR3 expression in the aging rat medial PFC.
• To determine if GCPII inhibition using 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) can enhance working memory in young and aged rats.

Main Methods:

• Examined GCPII and mGluR3 protein expression in the medial PFC of young and aged rats.
• Administered the GCPII inhibitor 2-MPPA systemically and locally into the medial PFC.
• Assessed working memory performance using behavioral tests.

Main Results:

• GCPII protein was found on neurons, astrocytes, and microglia in the medial PFC, with levels increasing with age.
• Systemic administration of 2-MPPA significantly improved working memory in both young and aged rats.
• Local infusion of 2-MPPA into the medial PFC also enhanced working memory performance.

Conclusions:

• GCPII is prominently expressed on neurons in the medial PFC and its levels increase with age.
• Inhibition of GCPII with 2-MPPA effectively improves working memory, irrespective of age.
• GCPII inhibitors represent a promising therapeutic strategy for cognitive disorders associated with aging and inflammation.