Impaired bidirectional NMDA receptor dependent synaptic plasticity in the dentate gyrus of adult female Fmr1 heterozygous knockout mice

Yau, Suk-Yu; Bostrom, Crystal A.; Chiu, Jason; Fontaine, Christine J.; Sawchuk, S.; Meconi, Alicia; Wortman, Ryan C.; Truesdell, E.; Truesdell, Aaron; Chiu, Christine L; Hryciw, Brett N.; Eadie, Brennan D.; Ghilan, Mohamed; Christie, Brian R.

doi:10.1016/j.nbd.2016.09.012

Cited by 29 publications

(16 citation statements)

References 46 publications

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“…On the other hand, younger granule neurons that reside in the inner GCL, did not show a significant change in dendritic complexity, although they did show a trend toward a reduction in NMDAR EPSCs induced by the lack of FMRP. These data further support our previous findings indicating that Fmr1 KO mice present a dysfunction in NMDAR in the hippocampal DG (Bostrom et al, 2015; Yau et al, 2016a), and show for the first time that these deficits are preferentially associated with a reduction in dendritic arborization in a specific population of granule cells in the outer GCL.…”

Section: Discussionsupporting

confidence: 92%

Fragile-X Syndrome Is Associated With NMDA Receptor Hypofunction and Reduced Dendritic Complexity in Mature Dentate Granule Cells

Yau

Bettio

Chiu

et al. 2019

Front. Mol. Neurosci.

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Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. It is caused by the overexpansion of cytosine-guanine-guanine (CGG) trinucleotide in Fmr1 gene, resulting in complete loss of the fragile X mental retardation protein (FMRP). Previous studies using Fmr1 knockout (Fmr1 KO) mice have suggested that a N-methyl-D-aspartate receptors (NMDAR) hypofunction in the hippocampal dentate gyrus may partly contribute to cognitive impairments in FXS. Since activation of NMDAR plays an important role in dendritic arborization during neuronal development, we examined whether deficits in NMDAR function are associated with alterations in dendritic complexity in the hippocampal dentate region. The dentate granule cell layer (GCL) presents active postnatal neurogenesis, and consists of a heterogenous neuronal population with gradient ages from the superficial to its deep layer. Here, we show that neurons with multiple primary dendrites that reside in the outer GCL of Fmr1 KO mice display significantly smaller NMDAR excitatory post-synaptic currents (EPSCs) and a higher α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to NMDA ratio in comparison to their wild-type counterparts. These deficits were associated with a significant decrease in dendritic complexity, with both dendritic length and number of intersections being significantly reduced. In contrast, although neurons with a single primary dendrite resided in the inner GCL of Fmr1 KO mice had a trend toward a reduction in NMDAR EPSCs and a higher AMPA/NMDA ratio, no alterations were found in dendritic complexity at this developmental stage. Our data indicate that the loss of FMRP causes NMDAR deficits and reduced dendritic complexity in granule neurons with multiple primary dendrites which are thought to be more mature in the GCL.

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Section: Discussionsupporting

confidence: 92%

Fragile-X Syndrome Is Associated With NMDA Receptor Hypofunction and Reduced Dendritic Complexity in Mature Dentate Granule Cells

Yau

Bettio

Chiu

et al. 2019

Front. Mol. Neurosci.

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“…The lack of FMRP in mouse and rat KO models have been previously associated with impaired functionality of DG and hippocampal-dependent spatial memory ( Franklin et al, 2014 ; Hébert et al, 2014 ; Yau et al, 2016 ) with both affected during normal aging in mammals ( Lister and Barnes, 2009 ). In the current study, FMRP levels were analyzed in the DG of young (17 weeks) and aging (22 months) rats and the results were confirmed by three different methodological approaches – quantitative proteomics, immunoblotting, and immunofluorescence microscopy.…”

Section: Discussionmentioning

confidence: 99%

Reduced Levels of the Synaptic Functional Regulator FMRP in Dentate Gyrus of the Aging Sprague-Dawley Rat

Šmidák

Sialana

Kristofova

et al. 2017

Front. Aging Neurosci.

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Fragile X mental retardation protein (FMRP) encoded by Fragile X mental retardation 1 (FMR1) gene is a RNA-binding regulator of mRNA translation, transport and stability with multiple targets responsible for proper synaptic function. Epigenetic silencing of FMR1 gene expression leads to the development of Fragile X syndrome (FXS) that is characterized by intellectual disability and other behavioral problems including autism. In the rat FXS model, the lack of FMRP caused a deficit in hippocampal-dependent memory. However, the hippocampal changes of FMRP in aging rats are not fully elucidated. The current study addresses the changes in FMRP levels in dentate gyrus (DG) from young (17 weeks) and aging (22 months) Sprague – Dawley rats. The aging animal group showed significant decline in spatial reference memory. Protein samples from five rats per each group were analyzed by quantitative proteomic analysis resulting in 153 significantly changed proteins. FMRP showed significant reduction in aging animals which was confirmed by immunoblotting and immunofluorescence microscopy. Furthermore, bioinformatic analysis of the differential protein dataset revealed several functionally related protein groups with individual interactions with FMRP. These include high representation of the RNA translation and processing machinery connected to FMRP and other RNA-binding regulators including CAPRIN1, the members of Pumilio (PUM) and CUG-BP, Elav-like (CELF) family, and YTH N(6)-methyladenosine RNA-binding proteins (YTHDF). The results of the current study point to the important role of FMRP and regulation of RNA processing in the rat DG and memory decline during the aging process.

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“…The adult offspring mice were pre-handled for 7 days to reduce the handling stress as previously performed (Yau et al, 2016). On the next day, they were acclimatized to the behavioral test room for 2 h and then to the empty temporal order testing apparatus for 15 min (Width × Length × Height: 40 cm × 40 cm × 30 cm).…”

Section: Methodsmentioning

confidence: 99%

“…Exploration ratio of the objects was calculated as (exploration time of object 1 or 3)/(exploration time of object 1 + 3). Exploration index was calculated as (exploration time of object 1 – 3)/(exploration time of object 1 + 3) (Yau et al, 2016).…”

Section: Methodsmentioning

confidence: 99%

Effects of Maternal Voluntary Wheel Running During Pregnancy on Adult Hippocampal Neurogenesis, Temporal Order Memory, and Depression-Like Behavior in Adult Female and Male Offspring

et al. 2019

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Research suggests that maternal exercise in pregnancy may have beneficial effects on the brain function of offspring. This study sought to determine if voluntary wheel running during pregnancy improves depression-like behavior, temporal order memory, and hippocampal neurogenesis in both female and male offspring mice. Pregnant mice were allowed to run voluntarily by introducing running wheels into the housing cages throughout the gestational period. Male and female mice offspring at the age of 8- to 9-week-old were then tested on the temporal order task and forced swim test, then euthanized for immunostaining for examining adult hippocampal cell proliferation and neuronal differentiation. Results showed that both male and female pups had reduced depression-like behavior, while only male offspring demonstrated improvement in temporal order memory. Immunostaining revealed that male offspring showed an increase in the number of immature neurons in the ventral hippocampus, whereas female offspring showed enhanced cell proliferation in the dorsal hippocampus. These findings indicate that maternal voluntary wheel running benefits both female and male offspring on reducing depression-like behavior, but with gender effect on promoting hippocampal cell proliferation, neuronal differentiation, and temporal order memory.

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Impaired bidirectional NMDA receptor dependent synaptic plasticity in the dentate gyrus of adult female Fmr1 heterozygous knockout mice

Cited by 29 publications

References 46 publications

Fragile-X Syndrome Is Associated With NMDA Receptor Hypofunction and Reduced Dendritic Complexity in Mature Dentate Granule Cells

Fragile-X Syndrome Is Associated With NMDA Receptor Hypofunction and Reduced Dendritic Complexity in Mature Dentate Granule Cells

Reduced Levels of the Synaptic Functional Regulator FMRP in Dentate Gyrus of the Aging Sprague-Dawley Rat

Effects of Maternal Voluntary Wheel Running During Pregnancy on Adult Hippocampal Neurogenesis, Temporal Order Memory, and Depression-Like Behavior in Adult Female and Male Offspring

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