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Cognition, learning behaviour and hippocampal synaptic plasticity are not disrupted in mice over-expressing the cholesterol transporter ABCG1.

Parkinson PF, Kannangara TS, Eadie BD, Burgess BL, Wellington CL, Christie BR - Lipids Health Dis (2009)

Bottom Line: Extra copies of the genes on chromosome 21 may also play an important role in the accelerated onset of AD in DS individuals.Growing evidence suggests an important function for cholesterol in the pathogenesis of AD, particularly in APP metabolism and production of A beta peptides.The ATP-Binding Cassette-G1 (ABCG1) transporter is located on chromosome 21, and participates in the maintenance of tissue cholesterol homeostasis.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada. parkinsonpam@gmail.com

ABSTRACT

Background: Cognitive deficits are a hallmark feature of both Down Syndrome (DS) and Alzheimer's Disease (AD). Extra copies of the genes on chromosome 21 may also play an important role in the accelerated onset of AD in DS individuals. Growing evidence suggests an important function for cholesterol in the pathogenesis of AD, particularly in APP metabolism and production of A beta peptides. The ATP-Binding Cassette-G1 (ABCG1) transporter is located on chromosome 21, and participates in the maintenance of tissue cholesterol homeostasis.

Results: To assess the role of ABCG1 in DS-related cognition, we evaluated the cognitive performance of mice selectively over-expressing the ABCG1 gene from its endogenous regulatory signals. Both wild-type and ABCG1 transgenic mice performed equivalently on several behavioral tests, including measures of anxiety, as well as on reference and working memory tasks. No deficits in hippocampal CA1 synaptic plasticity as determined with electrophysiological studies were apparent in mice over-expressing ABCG1.

Conclusion: These findings indicate that although ABCG1 may play a role in maintaining cellular or tissue cholesterol homeostasis, it is unlikely that excess ABCG1 expression contributes to the cognitive deficits in DS individuals.

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ABCG1 over-expression does not impact spatial reference memory or synaptic plasticity. The Morris Water Maze was employed to assess spatial reference memory in wild-type (WT; n = 11) and ABCG1 BAC Tg (Tg; n = 11) animals. (A) Latency to platform. Each point represents an average of 4 daily trials during the training period. No significant difference was observed between the groups in the time taken to find the hidden platform. (B) Probe trial results from a single-trial test. Both control and ABCG1 over-expressing groups showed similar preference for the North (N) quadrant, which contained the platform on training trials. All p values are non-significant. (C) In vitro electrophysiology was performed on 350 μm thick hippocampal slices derived from aged mice over-expressing ABCG1 (Tg) and wild-type (WT) littermates. High frequency stimulation (HFS) was applied to the Schaeffer collaterals to induce LTP in the CA1 region. No significant difference was observed between wild-type and transgenic mice. (D) Two stimuli were applied to the Schaeffer collaterals, including paired-pulse facilitation in the CA1 region, before and after the HFS tetanus protocol. No significant differences were observed between wild-type and transgenic mice, indicating that presynaptic release was unaffected by HFS in either mouse phenotype.
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Figure 3: ABCG1 over-expression does not impact spatial reference memory or synaptic plasticity. The Morris Water Maze was employed to assess spatial reference memory in wild-type (WT; n = 11) and ABCG1 BAC Tg (Tg; n = 11) animals. (A) Latency to platform. Each point represents an average of 4 daily trials during the training period. No significant difference was observed between the groups in the time taken to find the hidden platform. (B) Probe trial results from a single-trial test. Both control and ABCG1 over-expressing groups showed similar preference for the North (N) quadrant, which contained the platform on training trials. All p values are non-significant. (C) In vitro electrophysiology was performed on 350 μm thick hippocampal slices derived from aged mice over-expressing ABCG1 (Tg) and wild-type (WT) littermates. High frequency stimulation (HFS) was applied to the Schaeffer collaterals to induce LTP in the CA1 region. No significant difference was observed between wild-type and transgenic mice. (D) Two stimuli were applied to the Schaeffer collaterals, including paired-pulse facilitation in the CA1 region, before and after the HFS tetanus protocol. No significant differences were observed between wild-type and transgenic mice, indicating that presynaptic release was unaffected by HFS in either mouse phenotype.

Mentions: Mice expressing the ABCG1 BAC transgene were next evaluated against wild-type littermates on the Morris Water Maze spatial reference memory task. The task consisted of a 5-day acquisition phase in which mice were given 4 trials per day and a maximum time of 60 seconds per trial to locate a platform fixed in the North quadrant. Twenty-four hours later, a probe trial was administered to test recall of the platform location. ABCG1 BAC Tg mice displayed nearly identical average escape latency, or time to locate the platform, over each day of acquisition as compared to wild-type animals, and the learning curve was very similar (Figure 3). These results indicate that ABCG1 over-expression does not significantly affect learning during the acquisition phase of this water maze task. Repeated-measures ANOVA revealed a significant effect of training day, (p < 0.0001), but not group (p = 0.67). Performance on the single-trial probe test was also comparable between groups, with both wild-type and ABCG1 BAC Tg mice spending the greatest amount of time searching in the probe quadrant (North), which previously contained the platform during training days. Both groups displayed strong preference for the North quadrant, indicating that both wild-type and ABCG1 BAC Tg mice were capable of learning the task thoroughly, and were able to remember visual cues associated with the platform location during training trials. Additionally, the comparable performance of ABCG1 BAC Tg and wild-type mice on both learning during the acquisition phase or on memory recall in the probe trial, also suggests that over-expression of ABCG1 alone does not negatively affect hippocampal neuron function involved in the learning and memory required for this task.


Cognition, learning behaviour and hippocampal synaptic plasticity are not disrupted in mice over-expressing the cholesterol transporter ABCG1.

Parkinson PF, Kannangara TS, Eadie BD, Burgess BL, Wellington CL, Christie BR - Lipids Health Dis (2009)

ABCG1 over-expression does not impact spatial reference memory or synaptic plasticity. The Morris Water Maze was employed to assess spatial reference memory in wild-type (WT; n = 11) and ABCG1 BAC Tg (Tg; n = 11) animals. (A) Latency to platform. Each point represents an average of 4 daily trials during the training period. No significant difference was observed between the groups in the time taken to find the hidden platform. (B) Probe trial results from a single-trial test. Both control and ABCG1 over-expressing groups showed similar preference for the North (N) quadrant, which contained the platform on training trials. All p values are non-significant. (C) In vitro electrophysiology was performed on 350 μm thick hippocampal slices derived from aged mice over-expressing ABCG1 (Tg) and wild-type (WT) littermates. High frequency stimulation (HFS) was applied to the Schaeffer collaterals to induce LTP in the CA1 region. No significant difference was observed between wild-type and transgenic mice. (D) Two stimuli were applied to the Schaeffer collaterals, including paired-pulse facilitation in the CA1 region, before and after the HFS tetanus protocol. No significant differences were observed between wild-type and transgenic mice, indicating that presynaptic release was unaffected by HFS in either mouse phenotype.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2654451&req=5

Figure 3: ABCG1 over-expression does not impact spatial reference memory or synaptic plasticity. The Morris Water Maze was employed to assess spatial reference memory in wild-type (WT; n = 11) and ABCG1 BAC Tg (Tg; n = 11) animals. (A) Latency to platform. Each point represents an average of 4 daily trials during the training period. No significant difference was observed between the groups in the time taken to find the hidden platform. (B) Probe trial results from a single-trial test. Both control and ABCG1 over-expressing groups showed similar preference for the North (N) quadrant, which contained the platform on training trials. All p values are non-significant. (C) In vitro electrophysiology was performed on 350 μm thick hippocampal slices derived from aged mice over-expressing ABCG1 (Tg) and wild-type (WT) littermates. High frequency stimulation (HFS) was applied to the Schaeffer collaterals to induce LTP in the CA1 region. No significant difference was observed between wild-type and transgenic mice. (D) Two stimuli were applied to the Schaeffer collaterals, including paired-pulse facilitation in the CA1 region, before and after the HFS tetanus protocol. No significant differences were observed between wild-type and transgenic mice, indicating that presynaptic release was unaffected by HFS in either mouse phenotype.
Mentions: Mice expressing the ABCG1 BAC transgene were next evaluated against wild-type littermates on the Morris Water Maze spatial reference memory task. The task consisted of a 5-day acquisition phase in which mice were given 4 trials per day and a maximum time of 60 seconds per trial to locate a platform fixed in the North quadrant. Twenty-four hours later, a probe trial was administered to test recall of the platform location. ABCG1 BAC Tg mice displayed nearly identical average escape latency, or time to locate the platform, over each day of acquisition as compared to wild-type animals, and the learning curve was very similar (Figure 3). These results indicate that ABCG1 over-expression does not significantly affect learning during the acquisition phase of this water maze task. Repeated-measures ANOVA revealed a significant effect of training day, (p < 0.0001), but not group (p = 0.67). Performance on the single-trial probe test was also comparable between groups, with both wild-type and ABCG1 BAC Tg mice spending the greatest amount of time searching in the probe quadrant (North), which previously contained the platform during training days. Both groups displayed strong preference for the North quadrant, indicating that both wild-type and ABCG1 BAC Tg mice were capable of learning the task thoroughly, and were able to remember visual cues associated with the platform location during training trials. Additionally, the comparable performance of ABCG1 BAC Tg and wild-type mice on both learning during the acquisition phase or on memory recall in the probe trial, also suggests that over-expression of ABCG1 alone does not negatively affect hippocampal neuron function involved in the learning and memory required for this task.

Bottom Line: Extra copies of the genes on chromosome 21 may also play an important role in the accelerated onset of AD in DS individuals.Growing evidence suggests an important function for cholesterol in the pathogenesis of AD, particularly in APP metabolism and production of A beta peptides.The ATP-Binding Cassette-G1 (ABCG1) transporter is located on chromosome 21, and participates in the maintenance of tissue cholesterol homeostasis.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada. parkinsonpam@gmail.com

ABSTRACT

Background: Cognitive deficits are a hallmark feature of both Down Syndrome (DS) and Alzheimer's Disease (AD). Extra copies of the genes on chromosome 21 may also play an important role in the accelerated onset of AD in DS individuals. Growing evidence suggests an important function for cholesterol in the pathogenesis of AD, particularly in APP metabolism and production of A beta peptides. The ATP-Binding Cassette-G1 (ABCG1) transporter is located on chromosome 21, and participates in the maintenance of tissue cholesterol homeostasis.

Results: To assess the role of ABCG1 in DS-related cognition, we evaluated the cognitive performance of mice selectively over-expressing the ABCG1 gene from its endogenous regulatory signals. Both wild-type and ABCG1 transgenic mice performed equivalently on several behavioral tests, including measures of anxiety, as well as on reference and working memory tasks. No deficits in hippocampal CA1 synaptic plasticity as determined with electrophysiological studies were apparent in mice over-expressing ABCG1.

Conclusion: These findings indicate that although ABCG1 may play a role in maintaining cellular or tissue cholesterol homeostasis, it is unlikely that excess ABCG1 expression contributes to the cognitive deficits in DS individuals.

Show MeSH
Related in: MedlinePlus