Prodynorphin knockout mice demonstrate diminished age-associated impairment in spatial water maze performance

Nguyen, Xuan V.; Masse, James; Kumar, Ashok; Vijitruth, Rattanavijit; Kulik, Cynthia; Liu, Mei; Choi, Dong‐Young; Foster, Thomas C.; Usynin, I. F.; Bakalkin, Georgy; Bing, Guoying

doi:10.1016/j.bbr.2005.02.010

Cited by 44 publications

(35 citation statements)

References 48 publications

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“…Both subunits are closely linked with cognition and performances in spatial memory tasks [20,21,22,23], a form of cognition specifically altered in human and AD mouse models [24,25]. In line with our results, age-related cognitive deficits in the hippocampus-dependent Morris Water Maze spatial task are reduced in Pdyn KO mice [26]. Future studies will be necessary to determine the exact mechanism of the interactions of dynorphins with the glutamatergic system and to evaluate whether expression of these peptides correlated with memory impairments in AD mouse models and patients suffering from the disease.…”

Section: Discussionsupporting

confidence: 79%

Possible Role of Dynorphins in Alzheimer's Disease and Age-Related Cognitive Deficits

et al. 2013

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Background/Aims: Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated with cognitive deficits in rodents. Elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease (AD) patients, and prodynorphin (PDYN) gene polymorphisms might be linked to cognitive function in the elderly. Activation of κ-opioid receptors by dynorphins has been associated with stress-related memory impairments. Interestingly, these peptides can also modulate glutamate neurotransmission and may affect synaptic plasticity underlying memory formation. N-methyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA) ionotropic glutamate receptor levels generally decrease with aging, and their function is impaired in AD. Methods: Here, we compared the impact of aging on ionotropic glutamate receptor levels in the hippocampal formation of wild-type (WT) and Pdyn knock-out (KO) mice. Results: We observed a significant reduction in GluR1 and GluR2 AMPA receptor subunits in the hippocampal formation of 18- to 25-month-old WT mice in comparison with 6-month-old mice. Conversely, the GluR1 protein level was maintained in old Pdyn KO mice, and the NMDA NR2B subunit level was increased by 42% when compared to old WT animals. Conclusions: These results suggest that elevated dynorphin expression occurring during aging and AD may mediate cognitive deficits by altering the glutamatergic system integrity.

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Section: Discussionsupporting

confidence: 79%

Possible Role of Dynorphins in Alzheimer's Disease and Age-Related Cognitive Deficits

et al. 2013

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“…These effects appear to be relevant for processing of information associated with learning and memory. Behavioral data obtained with synthetic dynorphins and with prodynorphin deficient mice support this notion (Kameyama et al, 1994;Ukai et al, 1996;Hiramatsu et al, 1998Wall and Messier, 2000;Nguyen et al, 2005).…”

Section: Introductionmentioning

confidence: 67%

“…Consistently, prodynorphin knockout mice demonstrated diminished age-associated impairment in spatial water maze performance suggesting adverse actions of endogenous dynorphins. Endogenous dynorphins are upregulated with age and, consistently, less impairment was observed in aged prodynorphin-deficient mice (Nguyen et al, 2005).…”

Section: Discussionmentioning

confidence: 88%

Big Dynorphin, a Prodynorphin-Derived Peptide Produces NMDA Receptor-Mediated Effects on Memory, Anxiolytic-Like and Locomotor Behavior in Mice

Kuzmin

Madjid

Terenius

et al. 2005

Neuropsychopharmacol

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Effects of big dynorphin (Big Dyn), a prodynorphin-derived peptide consisting of dynorphin A (Dyn A) and dynorphin B (Dyn B) on memory function, anxiety, and locomotor activity were studied in mice and compared to those of Dyn A and Dyn B. All peptides administered i.c.v. increased step-through latency in the passive avoidance test with the maximum effective doses of 2.5, 0.005, and 0.7 nmol/animal, respectively. Effects of Big Dyn were inhibited by MK 801 (0.1 mg/kg), an NMDA ion-channel blocker whereas those of dynorphins A and B were blocked by the k-opioid antagonist nor-binaltorphimine (6 mg/kg). Big Dyn (2.5 nmol) enhanced locomotor activity in the open field test and induced anxiolytic-like behavior both effects blocked by MK 801. No changes in locomotor activity and no signs of anxiolytic-like behavior were produced by dynorphins A and B. Big Dyn (2.5 nmol) increased time spent in the open branches of the elevated plus maze apparatus with no changes in general locomotion. Whereas dynorphins A and B (i.c.v., 0.05 and 7 nmol/animal, respectively) produced analgesia in the hot-plate test Big Dyn did not. Thus, Big Dyn differs from its fragments dynorphins A and B in its unique pattern of memory enhancing, locomotor-and anxiolytic-like effects that are sensitive to the NMDA receptor blockade. The findings suggest that Big Dyn has its own function in the brain different from those of the prodynorphin-derived peptides acting through k-opioid receptors.

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“…For example, chronic exposure to MOR agonists negatively impacts hippocampal function, defined here as hippocampal-dependent behaviors, while blockade of MOR and other opiate receptors enhances hippocampal function Newsom, 1989, Spain andNewsom, 1991). Supporting the role for MOR in hippocampal function, transgenic mice that lack MOR or endogenous MOR ligands have altered behavior in hippocampal-dependent tasks (Jamot et al, 2003, Jang et al, 2003, Nguyen et al, 2005, Sanders et al, 2005. These studies encourage more detailed exploration of how MOR regulates hippocampal structure and function.…”

Section: Introductionmentioning

confidence: 94%

Knockout of the mu opioid receptor enhances the survival of adult-generated hippocampal granule cell neurons

Harburg¹,

Hall²,

Harrist³

et al. 2007

Neuroscience

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Recent evidence suggests that mu opioid receptors (MOR) are key regulators of hippocampal structure and function. For example, exogenous MOR agonists morphine and heroin negatively impact hippocampal function and decrease adult hippocampal neurogenesis. Here we explored the role of MOR in the birth and survival of hippocampal progenitor cells by examining adult neurogenesis in mice that lack MOR. Adult male mice lacking exon 1 of MOR were injected with the S phase marker bromodeoxyuridine (BrdU) and sacrificed either two hours or four weeks later to evaluate proliferating and surviving BrdU-immunoreactive (IR) cells, respectively, in the adult hippocampal granule cell layer. WT, heterozygote, and homozygote mice did not differ in the number of BrdU-IR cells at a proliferation time point. However, four weeks after BrdU injection, heterozygote and homozygote mice had 57% and 54% more surviving BrdU-IR cells in the hippocampal granule cell layer as compared to WT mice. A decrease in apoptosis in the heterozygote and homozygote mice did not account for the difference in number of surviving BrdU-IR cells since there were no alterations in number of pyknotic, TUNEL-positive, or activated caspase 3-IR cells compared to WT. In concordance with the increased numbers of granule cells maturing into neurons, heterozygote and homozygote mice had larger hippocampal granule cell layers and increased numbers of granule cells. These findings indicate that MOR may play a role in regulating progenitor cell survival and more generally encourage further exploration of how MOR activation can influence hippocampal structure and function.

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Prodynorphin knockout mice demonstrate diminished age-associated impairment in spatial water maze performance

Cited by 44 publications

References 48 publications

Possible Role of Dynorphins in Alzheimer's Disease and Age-Related Cognitive Deficits

Possible Role of Dynorphins in Alzheimer's Disease and Age-Related Cognitive Deficits

Big Dynorphin, a Prodynorphin-Derived Peptide Produces NMDA Receptor-Mediated Effects on Memory, Anxiolytic-Like and Locomotor Behavior in Mice

Knockout of the mu opioid receptor enhances the survival of adult-generated hippocampal granule cell neurons

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