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Brivaracetam, but not ethosuximide, reverses memory impairments in an Alzheimer's disease mouse model.

Nygaard HB, Kaufman AC, Sekine-Konno T, Huh LL, Going H, Feldman SJ, Kostylev MA, Strittmatter SM - Alzheimers Res Ther (2015)

Bottom Line: The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models.Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Yale University School of Medicine, 800 Howard Avenue, New Haven, CT 06510 USA ; Cellular Neuroscience, Neurodegeneration, and Repair Program (CNNR), Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536 USA ; Division of Neurology, The University of British Columbia, Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z3 Canada.

ABSTRACT

Introduction: Recent studies have shown that several strains of transgenic Alzheimer's disease (AD) mice overexpressing the amyloid precursor protein (APP) have cortical hyperexcitability, and their results have suggested that this aberrant network activity may be a mechanism by which amyloid-β (Aβ) causes more widespread neuronal dysfunction. Specific anticonvulsant therapy reverses memory impairments in various transgenic mouse strains, but it is not known whether reduction of epileptiform activity might serve as a surrogate marker of drug efficacy for memory improvement in AD mouse models.

Methods: Transgenic AD mice (APP/PS1 and 3xTg-AD) were chronically implanted with dural electroencephalography electrodes, and epileptiform activity was correlated with spatial memory function and transgene-specific pathology. The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.

Results: We report that in two transgenic mouse models of AD (APP/PS1 and 3xTg-AD), the presence of spike-wave discharges (SWDs) correlated with impairments in spatial memory. Both ethosuximide and brivaracetam reduce mouse SWDs, but only brivaracetam reverses memory impairments in APP/PS1 mice.

Conclusions: Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models. Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs. Our data indicate that SWDs are not a reliable surrogate marker of appropriate target engagement for reversal of memory dysfunction in APP/PS1 mice.

No MeSH data available.


Related in: MedlinePlus

Presence of spike-wave discharges correlates with impairments in spatial memory in APP/PS1 and 3xTg-AD mice. Both strains of transgenic mice underwent Morris water maze testing immediately after continuous in vivo electroencephalography recording. (A) and (C) The presence of more than one spike-wave discharge (SWD) worsened the performance of 8- to 10-month-old APP/PS1 mice in the acquisition phase of the Morris water maze (A), and the same was true of 3xTg-AD mice (C) (*P = 0.039 and **P = 0.002 by repeated-measures analysis of variance with post hoc analysis). (B) and (D) A 48-hour probe trial showed an inverse relationship between frequency of SWDs and entries into the target area, defined as the platform area, during a 1-minute trial in APP/PS1 mice (B), but not in 3xTg-AD mice (D) (P = 0.005 and 0.39, respectively; Pearson correlation coefficient). WT: n = 8; APP/PS1 with SWDs: n = 8; APP/PS1 without SWDs: n = 9. 3xTg-AD mice included six females and four males. v1 through v4 indicate visible platform swim trials.
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Fig2: Presence of spike-wave discharges correlates with impairments in spatial memory in APP/PS1 and 3xTg-AD mice. Both strains of transgenic mice underwent Morris water maze testing immediately after continuous in vivo electroencephalography recording. (A) and (C) The presence of more than one spike-wave discharge (SWD) worsened the performance of 8- to 10-month-old APP/PS1 mice in the acquisition phase of the Morris water maze (A), and the same was true of 3xTg-AD mice (C) (*P = 0.039 and **P = 0.002 by repeated-measures analysis of variance with post hoc analysis). (B) and (D) A 48-hour probe trial showed an inverse relationship between frequency of SWDs and entries into the target area, defined as the platform area, during a 1-minute trial in APP/PS1 mice (B), but not in 3xTg-AD mice (D) (P = 0.005 and 0.39, respectively; Pearson correlation coefficient). WT: n = 8; APP/PS1 with SWDs: n = 8; APP/PS1 without SWDs: n = 9. 3xTg-AD mice included six females and four males. v1 through v4 indicate visible platform swim trials.

Mentions: Although several groups have reported epileptiform discharges in AD mice, it is not known to what extent these discharges affect the phenotypic manifestations in transgenic models. We correlated the presence of SWDs in APP/PS1 and 3xTg-AD mice with spatial memory function as measured with the Morris water maze test. In APP/PS1 mice, the presence of SWDs measured prior to memory testing was associated with worsened performance in the acquisition phase of the Morris water maze (Figure 2A). Analysis of swim path length corroborated these findings (Additional file 1: Figure S1A). After 48 hours, the mice were tested for long-term memory in the probe trial. A modest inverse relationship between the number of entries in the correct target area and the number of SWDs was seen (Figure 2B). Similar findings were seen in 3xTg-AD mice, with the presence of SWDs correlating with spatial memory performance (Figure 2C). However, we did not see a correlation in the delayed probe trial between SWDs and the number of correct target entries in 3xTg-AD mice (Figure 2D), and path length analysis did not indicate a difference in memory performance of 3xTg-AD mice with SWDs compared with mice without them (Additional file 1: Figure S1D). Thus, the correlation between SWDs and spatial memory performance was less robust in 3xTg-AD transgenic mice compared with APP/PS1 mice. Although rare, SWDs can be associated with behavioral arrest that could interfere with the results of the Morris water maze test. To assess whether reduced latency to the platform observed in the transgenic AD mice with SWDs was due to excessive freezing or reduced swim speed, we measured swim speed and average resting time in addition to platform latency. The swim speed and rest times did not differ between groups (Additional file 1: Figure S1).Figure 2


Brivaracetam, but not ethosuximide, reverses memory impairments in an Alzheimer's disease mouse model.

Nygaard HB, Kaufman AC, Sekine-Konno T, Huh LL, Going H, Feldman SJ, Kostylev MA, Strittmatter SM - Alzheimers Res Ther (2015)

Presence of spike-wave discharges correlates with impairments in spatial memory in APP/PS1 and 3xTg-AD mice. Both strains of transgenic mice underwent Morris water maze testing immediately after continuous in vivo electroencephalography recording. (A) and (C) The presence of more than one spike-wave discharge (SWD) worsened the performance of 8- to 10-month-old APP/PS1 mice in the acquisition phase of the Morris water maze (A), and the same was true of 3xTg-AD mice (C) (*P = 0.039 and **P = 0.002 by repeated-measures analysis of variance with post hoc analysis). (B) and (D) A 48-hour probe trial showed an inverse relationship between frequency of SWDs and entries into the target area, defined as the platform area, during a 1-minute trial in APP/PS1 mice (B), but not in 3xTg-AD mice (D) (P = 0.005 and 0.39, respectively; Pearson correlation coefficient). WT: n = 8; APP/PS1 with SWDs: n = 8; APP/PS1 without SWDs: n = 9. 3xTg-AD mice included six females and four males. v1 through v4 indicate visible platform swim trials.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4419386&req=5

Fig2: Presence of spike-wave discharges correlates with impairments in spatial memory in APP/PS1 and 3xTg-AD mice. Both strains of transgenic mice underwent Morris water maze testing immediately after continuous in vivo electroencephalography recording. (A) and (C) The presence of more than one spike-wave discharge (SWD) worsened the performance of 8- to 10-month-old APP/PS1 mice in the acquisition phase of the Morris water maze (A), and the same was true of 3xTg-AD mice (C) (*P = 0.039 and **P = 0.002 by repeated-measures analysis of variance with post hoc analysis). (B) and (D) A 48-hour probe trial showed an inverse relationship between frequency of SWDs and entries into the target area, defined as the platform area, during a 1-minute trial in APP/PS1 mice (B), but not in 3xTg-AD mice (D) (P = 0.005 and 0.39, respectively; Pearson correlation coefficient). WT: n = 8; APP/PS1 with SWDs: n = 8; APP/PS1 without SWDs: n = 9. 3xTg-AD mice included six females and four males. v1 through v4 indicate visible platform swim trials.
Mentions: Although several groups have reported epileptiform discharges in AD mice, it is not known to what extent these discharges affect the phenotypic manifestations in transgenic models. We correlated the presence of SWDs in APP/PS1 and 3xTg-AD mice with spatial memory function as measured with the Morris water maze test. In APP/PS1 mice, the presence of SWDs measured prior to memory testing was associated with worsened performance in the acquisition phase of the Morris water maze (Figure 2A). Analysis of swim path length corroborated these findings (Additional file 1: Figure S1A). After 48 hours, the mice were tested for long-term memory in the probe trial. A modest inverse relationship between the number of entries in the correct target area and the number of SWDs was seen (Figure 2B). Similar findings were seen in 3xTg-AD mice, with the presence of SWDs correlating with spatial memory performance (Figure 2C). However, we did not see a correlation in the delayed probe trial between SWDs and the number of correct target entries in 3xTg-AD mice (Figure 2D), and path length analysis did not indicate a difference in memory performance of 3xTg-AD mice with SWDs compared with mice without them (Additional file 1: Figure S1D). Thus, the correlation between SWDs and spatial memory performance was less robust in 3xTg-AD transgenic mice compared with APP/PS1 mice. Although rare, SWDs can be associated with behavioral arrest that could interfere with the results of the Morris water maze test. To assess whether reduced latency to the platform observed in the transgenic AD mice with SWDs was due to excessive freezing or reduced swim speed, we measured swim speed and average resting time in addition to platform latency. The swim speed and rest times did not differ between groups (Additional file 1: Figure S1).Figure 2

Bottom Line: The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models.Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Yale University School of Medicine, 800 Howard Avenue, New Haven, CT 06510 USA ; Cellular Neuroscience, Neurodegeneration, and Repair Program (CNNR), Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536 USA ; Division of Neurology, The University of British Columbia, Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z3 Canada.

ABSTRACT

Introduction: Recent studies have shown that several strains of transgenic Alzheimer's disease (AD) mice overexpressing the amyloid precursor protein (APP) have cortical hyperexcitability, and their results have suggested that this aberrant network activity may be a mechanism by which amyloid-β (Aβ) causes more widespread neuronal dysfunction. Specific anticonvulsant therapy reverses memory impairments in various transgenic mouse strains, but it is not known whether reduction of epileptiform activity might serve as a surrogate marker of drug efficacy for memory improvement in AD mouse models.

Methods: Transgenic AD mice (APP/PS1 and 3xTg-AD) were chronically implanted with dural electroencephalography electrodes, and epileptiform activity was correlated with spatial memory function and transgene-specific pathology. The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.

Results: We report that in two transgenic mouse models of AD (APP/PS1 and 3xTg-AD), the presence of spike-wave discharges (SWDs) correlated with impairments in spatial memory. Both ethosuximide and brivaracetam reduce mouse SWDs, but only brivaracetam reverses memory impairments in APP/PS1 mice.

Conclusions: Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models. Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs. Our data indicate that SWDs are not a reliable surrogate marker of appropriate target engagement for reversal of memory dysfunction in APP/PS1 mice.

No MeSH data available.


Related in: MedlinePlus