Inhibition of glutamate-carboxypeptidase-II in dorsolateral prefrontal cortex: potential therapeutic target for neuroinflammatory cognitive disorders

Abstract

Glutamate carboxypeptidase-II (GCPII) expression in brain is increased by inflammation, e.g. by COVID19 infection, where it reduces NAAG stimulation of metabotropic glutamate receptor type 3 (mGluR3). GCPII-mGluR3 signaling is increasingly linked to higher cognition, as genetic alterations that weaken mGluR3 or increase GCPII signaling are associated with impaired cognition in humans. Recent evidence from macaque dorsolateral prefrontal cortex (dlPFC) shows that mGluR3 are expressed on dendritic spines, where they regulate cAMP-PKA opening of potassium (K+) channels to enhance neuronal firing during working memory. However, little is known about GCPII expression and function in the primate dlPFC, despite its relevance to inflammatory disorders. The present study used multiple label immunofluorescence and immunoelectron microscopy to localize GCPII in aging macaque dlPFC, and examined the effects of GCPII inhibition on dlPFC neuronal physiology and working memory function. GCPII was observed in astrocytes as expected, but also on neurons, including extensive expression in dendritic spines. Recordings in dlPFC from aged monkeys performing a working memory task found that iontophoresis of the GCPII inhibitors 2-MPPA or 2-PMPA markedly increased working memory-related neuronal firing and spatial tuning, enhancing neural representations. These beneficial effects were reversed by an mGluR2/3 antagonist, or by a cAMP-PKA activator, consistent with mGluR3 inhibition of cAMP-PKA-K+ channel signaling. Systemic administration of the brain penetrant inhibitor, 2-MPPA, significantly improved working memory performance without apparent side effects, with largest effects in the oldest monkeys. Taken together, these data endorse GCPII inhibition as a potential strategy for treating cognitive disorders associated with aging and/or neuroinflammation.

Scientific rationale for the use of α2A-adrenoceptor agonists in treating neuroinflammatory cognitive disorders

“…These receptors are localized on layer III spines, and they inhibit cAMPcalcium opening of K + channels, strengthening network connectivity and enhancing the dlPFC neuronal firing needed for higher cognition. mGluR3 are primarily post-synaptic in the primate dlPFC, and are not only stimulated by glutamate, but by N-acetylaspartylglutamate (NAAG), which is co-released with glutamate and is selective for mGluR3 [85,86]. α2A-ARs are often pre-synaptic receptors, but also play a major post-synaptic role in primate dlPFC where they are concentrated on dendritic spines near HCN channels [71].…”

“…GCPII is synthesized and released by glia, including large increases in GCPII expression by reactive microglia under conditions of inflammation [91,92]. Physiological studies in aged monkeys show that GCPII markedly lowers the dlPFC neuronal firing needed for higher cognition [86]. PDE4s are also lost with age in primate dlPFC [88,93], and this may involve MK2 inflammatory signaling unanchoring PDE4 from DISC1 [94].…”

Experimental approaches for altering the expression of Abeta‐degrading enzymes

“…As mentioned above, GCPII degrades the neurotransmitter NAAG. After NAAG is released from presynaptic terminals, its cleavage by GCPII (which is expressed by both neurons and astrocytes [Yang et al, 2022]) produces glutamate and N‐acetyl aspartate. Therefore, inhibition of GCPII activity reduces local glutamate production.…”

D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II

“…Glutamate carboxypeptidase II (GCPII), also known as prostate-specific membrane antigen (PSMA), is a type II transmembrane metallopeptidase encoded by the folate hydrolase (FOLH1) gene in humans [ 1 ]. Since its discovery in 1987 [ 2 ], its expression in different tissues such as the prostate, kidney [ 3 ], small intestine [ 4 , 5 ], and central and peripheral nervous system [ 6 , 7 , 8 ] has been reported. In the brain, GCPII catalyzes the hydrolysis of the neurotransmitter N -acetylaspartylglutamate (NAAG) to N -acetylaspartate (NAA) and glutamate [ 9 ], and multiple independent research groups have demonstrated the therapeutic benefit of inhibiting GCPII to treat neurological dysfunctions [ 6 , 7 , 8 ].…”

“…Since its discovery in 1987 [ 2 ], its expression in different tissues such as the prostate, kidney [ 3 ], small intestine [ 4 , 5 ], and central and peripheral nervous system [ 6 , 7 , 8 ] has been reported. In the brain, GCPII catalyzes the hydrolysis of the neurotransmitter N -acetylaspartylglutamate (NAAG) to N -acetylaspartate (NAA) and glutamate [ 9 ], and multiple independent research groups have demonstrated the therapeutic benefit of inhibiting GCPII to treat neurological dysfunctions [ 6 , 7 , 8 ]. Similarly, perturbation in GCPII expression has been reported in cancer neovasculature [ 10 ], tumor angiogenesis [ 11 ], as well as in inflammatory bowel disease [ 12 , 13 , 14 ].…”