Dissecting the age-related decline on spatial learning and memory tasks in rodent models: N-methyl-D-aspartate receptors and voltage-dependent Ca2+ channels in senescent synaptic plasticity

Foster, Thomas C.

doi:10.1016/j.pneurobio.2012.01.007

Cited by 147 publications

(170 citation statements)

References 360 publications

(593 reference statements)

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“…A positive correlation between V T and age was observed and so future studies, especially if involving poorly matched subgroups, should model this as a covariate in the analyses. This finding appears at odds with the agerelated declines in cerebral blood flow (39) and NMDA receptor function (40). However, it is possible that the relationship between 18 F-GE-179 V T and age is nonlinear.…”

Section: Discussionmentioning

confidence: 99%

Initial Evaluation of ¹⁸F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors

et al. 2014

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and 6 GE Healthcare plc, Amersham, United Kingdom N-methyl D-aspartate (NMDA) ion channels play a key role in a wide range of physiologic (e.g., memory and learning tasks) and pathologic processes (e.g., excitotoxicity). To date, suitable PET markers of NMDA ion channel activity have not been available. 18 F-GE-179 is a novel radioligand that selectively binds to the open/active state of the NMDA receptor ion channel, displacing the binding of 3 H-tenocyclidine from the intrachannel binding site with an affinity of 2.4 nM. No significant binding was observed with 10 nM GE-179 at 60 other neuroreceptors, channels, or transporters. We describe the kinetic behavior of the radioligand in vivo in humans. Methods: Nine healthy participants (6 men, 3 women; median age, 37 y) each underwent a 90-min PET scan after an intravenous injection of 18 F-GE-179. Continuous arterial blood sampling over the first 15 min was followed by discrete blood sampling over the duration of the scan. Brain radioactivity (KBq/mL) was measured in summation images created from the attenuation-and motion-corrected dynamic images. Metabolite-corrected parent plasma input functions were generated. We assessed the abilities of 1-, 2-, and 3-compartment models to kinetically describe cerebral time-activity curves using 6 bilateral regions of interest. Parametric volume-of-distribution (V T ) images were generated by voxelwise rank-shaping regularization of exponential spectral analysis (RS-ESA). Results: A 2-brain-compartment, 4-rate-constant model best described the radioligand's kinetics in normal gray matter of subjects at rest. At 30 min after injection, 37% of plasma radioactivity represented unmetabolized 18 F-GE-179. The highest mean levels of gray matter radioactivity were seen in the putamina and peaked at 7.5 min. A significant positive correlation was observed between K 1 and V T (Spearman ρ 5 0.398; P 5 0.003). Between-subject coefficients of variation of V T ranged between 12% and 16%. Voxelwise RS-ESA yielded similar V T s and coefficients of variation. Conclusion: 18 F-GE-179 exhibits high and rapid brain extraction, with a relatively homogeneous distribution in gray matter and acceptable between-subject variability. Despite its rapid peripheral metabolism, quantification of 18 F-GE-179 V T is feasible both within regions of interest and at the voxel level. The specificity of 18 F-GE-179 binding, however, requires further characterization with in vivo studies using activation and disease models.

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Section: Discussionmentioning

confidence: 99%

Initial Evaluation of ¹⁸F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors

et al. 2014

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“…Next we consider the possibility that reduced levels of neuromodulators in slices from aged rats limited the induction NMDAR-LTD. In CA1 and cortical synapses Gq-coupled receptors promote NMDAR-LTD (Choi et al, 2005;Huang et al, 2012), and this type of modulation is an attractive candidate substrate for the behavioral gating of LTD observed in vivo (Hagena and Manahan-Vaughan, 2011). We found that stimulation of ␣1 adrenergic receptors (coupled to Gq) with bath application of methoxamine (5 M during LFS), a manipulation that rescues the loss of NMDAR-LTD in the visual cortex after dark rearing (Guo et al, 2012), did not improve NMDAR-LTD in slices from AU rats (96.50 Ϯ 1.68% of LTD, n ϭ 6 slices, 2 rats; data not shown).…”

Section: Aging Reduces Nmdar-ltd In Both Aged Groups and Mglur-ltd Inmentioning

confidence: 99%

“…However, the central premise-that the NR2b subunit promotes LTD over LTP-has been challenged by several studies reporting that NR2b-containing receptors are not essential for LTD (Morishita et al, 2007), but rather promote LTP over LTD (Philpot et al, 2003;Barria and Malinow, 2005). Another possibility has invoked an age-dependent change in intracellular Ca 2ϩ homeostasis as a basis for reduced LTP and enhanced LTD, which is observed in the SC3 CA1 pathway of some rat models of aging (Burke and Barnes, 2006;Oh et al, 2010;Foster, 2012). Note, however, that both altered NMDAR subunit composition and altered Ca 2ϩ homeostasis would predict that NMDAR-LTP should also be affected.…”

Section: Mechanisms Of Altered Plasticity In the Aged A/c3 Ca3mentioning

confidence: 99%

“…A link between hyperactivity and impaired synaptic plasticity is further suggested by studies in sensory cortices, where levels of neural activity can profoundly alter the induction of LTD. In particular, manipulations that reduce the GABAergic inhibitory tone and increase cortical excitability impair the induction of NMDAR-dependent LTD; conversely, restoring normal cortical excitability also restores LTD induction (Choi et al, 2002). Thus, if a similar type of regulation operates in CA3, increased excitability could impair synaptic plasticity, contributing to network dysfunction.…”

Section: Mechanisms Of Altered Plasticity In the Aged A/c3 Ca3mentioning

confidence: 99%

“…Previous research, primarily conducted at the Schaffer collateral inputs to CA1 cells (SC3 CA1) has identified alterations in LTP and LTD that are associated with age-related cognitive decline (Landfield and Lynch, 1977;Deupree et al, 1993;Norris et al, 1996;Shankar et al, 1998;Schulz et al, 2002;Tombaugh et al, 2002;Burke and Barnes, 2006;Boric et al, 2008). While the SC3 CA1 pathway has been a preferred model to study the cellular basis of cognitive impairment because the mechanisms of LTP and LTD have been thoroughly characterized in normal young rats, a wealth of evidence at both the systems and molecular levels indicates that differences in cognitive aging are strongly evident in hippocampal circuits and subregions outside CA1.…”

Section: Introductionmentioning

confidence: 99%

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Integrity of mGluR-LTD in the Associative/Commissural Inputs to CA3 Correlates with Successful Aging in Rats

Yang

Megill

Ardiles

et al. 2013

Journal of Neuroscience

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The impact of aging on cognitive capabilities varies among individuals ranging from significant impairment to preservation of function on par with younger adults. Research on the neural basis for age-related memory decline has focused primarily on the CA1 region of the hippocampus. However, recent studies in elderly human and rodents indicate that individual differences in cognitive aging are more strongly tied to functional alterations in CA3 circuits. To examine synaptic plasticity in the CA3 region, we used aged rats behaviorally characterized in a hippocampal-dependent task to evaluate the status of long-term potentiation and long-term depression (LTP and LTD) in the associative/commissural pathway (A/C3 CA3), which provides the majority of excitatory input to CA3 pyramidal neurons. We found that, unlike in CA1 synapses, in A/C3 CA3 LTP is minimally affected by age. However, two forms of LTD, involving NMDA and metabotropic glutamate receptors (mGluR), are both greatly reduced in age-impaired rats. Age-unimpaired rats, in contrast, had intact mGluR LTD. These findings indicate that the integrity of mGluR-LTD at A/C3 CA3 inputs may play a crucial role in maintaining the performance of CA3 circuitry in aging.

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A Multifunctional Nanocarrier System for Highly Efficient and Targeted Delivery of Ketamine to NMDAR Sites for Improved Treatment of Depression

Tan

Gao

et al. 2023

Adv Healthcare Materials

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Ketamine (KA), commonly used as an anesthetic, is now widely studied as an antidepressant for the treatment of depression. However, due to its side effects, such as addiction and cognitive impairment, the dosage and frequency of (S)‐ketamine approved by the FDA for the treatment of refractory depression is very low, which limits its efficacy. Here, a new multifunctional nanocarrier system (AC‐RM@HA‐MS) with specific targeting capabilities is developed to improve the efficacy of KA treatment. KA‐loaded NPs (AC‐RM@HA‐MS‐KA) are constructed with a multilayer core–shell structure. KA‐loaded mesoporous silica NPs are prepared, conjugated with hyaluronic acid (HA) as pore gatekeepers, and sheathed with an RBC‐membrane (RM) for camouflage. Finally, the surface is tagged with bifunctional peptides (Ang‐2‐Con‐G, AC) to achieve specific targeting. One peptide (Ang‐2) is acted as a guide to facilitate the crossing of the blood–brain barrier (BBB), while the other (Con‐G) is functioned as a ligand for the targeted delivery of KA to the N‐methyl‐D‐aspartate receptor sites. Animal experiments reveal that AC‐RM@HA‐MS‐KA NPs effectively cross the BBB and directionally accumulate in the curing areas, thereby alleviating the depressive symptoms and improving the cognitive functions of depressed mice. After treatment, the depressed mice almost completely return to normal without obvious symptoms of addiction.

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Dissecting the age-related decline on spatial learning and memory tasks in rodent models: N-methyl-D-aspartate receptors and voltage-dependent Ca2+ channels in senescent synaptic plasticity

Cited by 147 publications

References 360 publications

Initial Evaluation of ¹⁸F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors

Initial Evaluation of ¹⁸F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors

Integrity of mGluR-LTD in the Associative/Commissural Inputs to CA3 Correlates with Successful Aging in Rats

A Multifunctional Nanocarrier System for Highly Efficient and Targeted Delivery of Ketamine to NMDAR Sites for Improved Treatment of Depression

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Dissecting the age-related decline on spatial learning and memory tasks in rodent models: N-methyl-D-aspartate receptors and voltage-dependent Ca2+ channels in senescent synaptic plasticity

Cited by 147 publications

References 360 publications

Initial Evaluation of 18F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors

Initial Evaluation of 18F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors

Integrity of mGluR-LTD in the Associative/Commissural Inputs to CA3 Correlates with Successful Aging in Rats

A Multifunctional Nanocarrier System for Highly Efficient and Targeted Delivery of Ketamine to NMDAR Sites for Improved Treatment of Depression

Contact Info

Product

Resources

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Initial Evaluation of ¹⁸F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors

Initial Evaluation of ¹⁸F-GE-179, a Putative PET Tracer for Activated N-Methyl d-Aspartate Receptors