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

2021 ◽  
Vol 13 ◽  
Author(s):  
Dibyadeep Datta ◽  
Shannon N. Leslie ◽  
Elizabeth Woo ◽  
Nishita Amancharla ◽  
Ayah Elmansy ◽  
...  
Keyword(s):  
Working Memory ◽  
Memory Performance ◽  
Cognitive Disorders ◽  
Glutamate Carboxypeptidase Ii ◽  
Prefrontal Cortical ◽  
Aging Rat ◽  
Medial Pfc ◽  
Improved Performance ◽  
Glutamate Carboxypeptidase ◽  
Pentanedioic Acid

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.

scholarly journals Effects of blocking mGluR5 on primate dorsolateral prefrontal cortical neuronal firing and working memory performance

2020 ◽  
Vol 238 (1) ◽  
pp. 97-106
Author(s):  
Sheng-Tao Yang ◽  
Min Wang ◽  
Veronica Galvin ◽  
Yang Yang ◽  
Amy F. T. Arnsten
Keyword(s):  
Working Memory ◽  
Cognitive Performance ◽  
Dose Response ◽  
Memory Performance ◽  
Cognitive Disorders ◽  
Neuronal Firing ◽  
Low Doses ◽  
Response Curves ◽  
Prefrontal Cortical ◽  
Dorsolateral Prefrontal

Abstract Rationale Metabotropic glutamate type 5 receptor (mGluR5) antagonists are under development for treating cognitive disorders such as Fragile X syndrome and Alzheimer’s disease, largely based on success in mouse models, where post-synaptic mGluR5 stimulation weakens synaptic functions in hippocampus. However, human trials of mGluR5 antagonists have yet to be successful. This may be due in part to the differing effects of mGluR5 in hippocampus vs. prefrontal cortex, as mGluR5 are primarily post-synaptic in rodent hippocampus, but are both pre- and post-synaptic in the dorsolateral prefrontal cortical (dlPFC) circuits known to subserve working memory. Objectives and methods The current study examined the effects of the selective mGluR5 negative allosteric modulator, MTEP (3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride), on neuronal firing and working memory performance in aging rhesus monkeys with naturally occurring impairments in neuronal firing and cognitive performance. Results We found that iontophoresis of MTEP directly onto dlPFC “Delay cells” had an inverted U dose-response, where low doses tended to enhance task-related firing, but higher doses suppressed neuronal firing. Similar effects were seen on cognitive performance following systemic MTEP administration (0.0001–0.1 mg/kg), with MTEP producing erratic dose-response curves. In the subset of monkeys (50%) that showed replicable improvement with MTEP, co-administration with the mGluR5 PAM, CDPPB (3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide), blocked MTEP beneficial effects, consistent with mGluR5 actions. Conclusions The mixed effects of MTEP on cognitive performance may arise from opposing actions at pre- vs. post-synaptic mGluR5 in dlPFC. These data from monkeys suggest that future clinical trials should include low doses, and identification of potential subgroup responders.

Does Strategic Memory Training Improve the Working Memory Performance of Younger and Older Adults?

2007 ◽  
Vol 54 (4) ◽  
pp. 311-320 ◽  
Author(s):  
Barbara Carretti ◽  
Erika Borella ◽  
Rossana De Beni
Keyword(s):  
Older Adults ◽  
Working Memory ◽  
Memory Performance ◽  
Memory Task ◽  
Memory Training ◽  
Control Groups ◽  
Improved Performance ◽  
Strategic Training ◽  
Strategic Memory ◽  
Experimental Group

Abstract. The paper examines the effect of strategic training on the performance of younger and older adults in an immediate list-recall and a working memory task. The experimental groups of younger and older adults received three sessions of memory training, teaching the use of mental images to improve the memorization of word lists. In contrast, the control groups were not instructed to use any particular strategy, but they were requested to carry out the memory exercises. The results showed that strategic training improved performance of both the younger and older experimental groups in the immediate list recall and in the working memory task. Of particular interest, the improvement in working memory performance of the older experimental group was comparable to that of the younger experimental group.

scholarly journals Recovery from impaired working memory performance during chronic Δ-9-tetrahydrocannabinol administration to adolescent rhesus monkeys

2019 ◽  
Vol 34 (2) ◽  
pp. 211-220
Author(s):  
Christopher D Verrico ◽  
David S Mathai ◽  
Hong Gu ◽  
Allan R Sampson ◽  
David A Lewis
Keyword(s):  
Working Memory ◽  
Rhesus Monkeys ◽  
Spatial Working Memory ◽  
Memory Performance ◽  
Residual Effects ◽  
Vehicle Group ◽  
Performance Accuracy ◽  
Comparable Performance ◽  
Improved Performance ◽  
And Performance

Background: The relationship between adolescent cannabis use and susceptibility to persistent cognitive impairments is poorly understood. Aims: We examined the effects of repeated exposure to Δ-9-tetrahydrocannabinol (THC) on reinforcement-related learning and performance of spatial working memory (WM) tasks of varying difficulty in adolescent monkeys. Methods: Seven pairs of male adolescent rhesus monkeys, matched for baseline cognitive performance, received vehicle or THC intravenously 5 days/week for 12 months. Performance on 4-item spatial WM trials was assessed throughout the 12-month study period. At the 6-month time point, more difficult novel and distractor 8-item spatial WM trials were added. Residual effects on performance were determined 23 or 71 h after THC or vehicle administration throughout the study. Results/outcomes: Relative to vehicle-exposed animals, repeated THC exposure was initially associated with significantly slower improvement in performance accuracy on 4-item spatial WM trials; however, this performance difference gradually diminished such that by month 12, accuracy did not significantly differ between vehicle and THC groups. Similarly, for the novel and distractor 8-item trials introduced at month 6, performance accuracy improved more slowly in the THC than in the vehicle group, despite comparable performance between groups on the 4-item task during this same period. Conclusions/interpretation: These findings suggest that compared to vehicle exposure, THC exposure during adolescence impairs the reinforcement-related learning process required for improved performance on spatial WM tasks, but this impairment might be overcome with continued training, even in the face of ongoing THC exposure.

scholarly journals Facilitation of spatial working memory performance following intra-prefrontal cortical administration of the adrenergic alpha1 agonist phenylephrine

2015 ◽  
Vol 232 (21-22) ◽  
pp. 4005-4016 ◽  
Author(s):  
Martha Hvoslef-Eide ◽  
C. A. Oomen ◽  
B. M. Fisher ◽  
C. J. Heath ◽  
T. W. Robbins ◽  
...  
Keyword(s):  
Working Memory ◽  
Spatial Working Memory ◽  
Memory Performance ◽  
Prefrontal Cortical

scholarly journals 11C-MCG: Synthesis, Uptake Selectivity, and Primate PET of a Probe for Glutamate Carboxypeptidase II (NAALADase)

2002 ◽  
Vol 1 (2) ◽  
pp. 153535002002021
Author(s):  
Martin G. Pomper ◽  
John L. Musachio ◽  
Jiazhong Zhang ◽  
Ursula Scheffel ◽  
Yun Zhou ◽  
...  
Keyword(s):  
Radiochemical Yield ◽  
Target Tissue ◽  
Glutamatergic Transmission ◽  
Glutamate Carboxypeptidase Ii ◽  
Quantitative Pet ◽  
Positron Emission ◽  
Glutamate Carboxypeptidase ◽  
Pentanedioic Acid ◽  
The Brain

Imaging of glutamate carboxypeptidase II (GCP II), also known as N-acetylated α-linked l-amino dipeptidase (NAALADase), may enable study of glutamatergic transmission, prostate cancer, and tumor neovasculature in vivo. Our goal was to develop a probe for GCP II for use with positron emission tomography (PET). Radiosynthesis of 11C–MeCys–C(O)–Glu or 11C-( S)-2-[3-(( R)-1-carboxy-2-methylsulfanyl-ethyl)-ureido]-pentanedioic acid (11C-MCG), an asymmetric urea and potent ( Ki = 1.9 nM) inhibitor of GCP II, was performed by C-11 methylation of the free thiol. Biodistribution of 11C-MCG was assayed in mice, and quantitative PET was performed in a baboon. 11C-MCG was obtained in 16% radiochemical yield at the end of synthesis with specific radioactivities over 167 GBq/mmol (4000 Ci/mmol) within 30 min after the end of bombardment. At 30 min postinjection, 11C-MCG showed 33.0 ± 5.1%, 0.4 ± 0.1%, and 1.1 ± 0.2% ID/g in mouse kidney (target tissue), muscle, and blood, respectively. Little radioactivity gained access to the brain. Blockade with unlabeled MCG or 2-(phosphonomethyl)pentanedioic acid (PMPA), another potent inhibitor of GCP II, provided sevenfold and threefold reductions, respectively, in binding to target tissue. For PET, distribution volumes (DVs) were 1.38 then 0.87 pre- and postblocker (PMPA). Little metabolism of 11C-MCG occurred in the mouse or baboon. These results suggest that 11C-MCG may be useful for imaging GCP II in the periphery.

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