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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

APP/PS1 mice have frequent epileptiform discharges. (A) Spontaneous generalized convulsive seizure, (B) spike-wave discharge (SWD) (arrows) and (C) single spike in a 10-month-old APP/PS1 mouse (arrows). The arrowheads indicate normal electroencephalogram background following single spike. (D) Quantification of SWDs in APP/PS1 mice compared with their wild-type (WT) littermates. (E) Quantification of single spikes does not show a difference between APP/PS1 mice and WT littermates (n = 8 for WT, 19 for APP/PS1). *P < 0.05 by Student’s t-test. WT, five females and three males; APP/PS1 mice with SWDs, four males and five females; APP/PS1 mice without SWDs, six females and four males. Calibration: SWD = 200 μV/0.5 s; spike = 200 μV/1 s.
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Fig1: APP/PS1 mice have frequent epileptiform discharges. (A) Spontaneous generalized convulsive seizure, (B) spike-wave discharge (SWD) (arrows) and (C) single spike in a 10-month-old APP/PS1 mouse (arrows). The arrowheads indicate normal electroencephalogram background following single spike. (D) Quantification of SWDs in APP/PS1 mice compared with their wild-type (WT) littermates. (E) Quantification of single spikes does not show a difference between APP/PS1 mice and WT littermates (n = 8 for WT, 19 for APP/PS1). *P < 0.05 by Student’s t-test. WT, five females and three males; APP/PS1 mice with SWDs, four males and five females; APP/PS1 mice without SWDs, six females and four males. Calibration: SWD = 200 μV/0.5 s; spike = 200 μV/1 s.

Mentions: Recently, authors have reported various types of epileptiform discharges in transgenic AD mice overexpressing APP. In the J20 model (APPswe,Ind), both generalized seizures and single spikes were reported [4], and APP/PS1 mice were found to have single spikes, clusters of SWDs and generalized seizures, when compared with nontransgenic littermate controls [5,18]. We have previously shown that 40% of aged APP/PS1 mice have convulsive seizures when recorded for 72 hours by continuous EEG video monitoring (Figure 1A) [6]. To further characterize epileptiform activity in transgenic AD mice, we assessed nineteen 8- to 10-month-old APP/PS1 mice using long-term in vivo EEG video monitoring. In addition to convulsive seizures, 9 (47%) of 19 APP/PS1 mice had frequent clusters of SWDs, compared with 0 of 8 of their wild-type littermates (Figure 1B,D). Using synchronized video analysis, a total of 240 hours of EEG were analyzed, and freezing behavior during the SWDs that might interfere with memory testing was quantified. Overall, only 82 SWDs were associated with brief behavioral arrest for the duration of the SWD, for a rate of less than one arrest per hour. In contrast with previous authors, we show that the frequency of single spikes is not transgene-dependent and that APP/PS1 mice do not differ from their wild-type littermates (Figure 1C,E). To assess EEG characteristics in a second AD mouse model, a limited cohort of ten 3xTg-AD mice aged 8 to 10 months underwent continuous in vivo EEG recording for 24 hours as described for APP/PS1 mice. None of the 3xTg-AD mice had convulsive seizures during the recording period. Four (40%) of ten of the 3xTg-AD mice had SWDs over a 12-hour period (11 ± 6 SWDs/hr). On the basis of EEG morphology, no differences in SWDs were observed between mouse strains, and the frequency of SWDs was not found to be significantly different between the two mouse models (APP/PS1 mean: 5 ± 1 SWDs/hr versus 3xTg-AD mean: 11 ± 6 SWDs/hr; P = 0.2 by Student’s t-test). Owing to the high frequency and concordance between transgenic lines, we focused on SWDs as the primary manifestation of epileptiform activity.Figure 1


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)

APP/PS1 mice have frequent epileptiform discharges. (A) Spontaneous generalized convulsive seizure, (B) spike-wave discharge (SWD) (arrows) and (C) single spike in a 10-month-old APP/PS1 mouse (arrows). The arrowheads indicate normal electroencephalogram background following single spike. (D) Quantification of SWDs in APP/PS1 mice compared with their wild-type (WT) littermates. (E) Quantification of single spikes does not show a difference between APP/PS1 mice and WT littermates (n = 8 for WT, 19 for APP/PS1). *P < 0.05 by Student’s t-test. WT, five females and three males; APP/PS1 mice with SWDs, four males and five females; APP/PS1 mice without SWDs, six females and four males. Calibration: SWD = 200 μV/0.5 s; spike = 200 μV/1 s.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: APP/PS1 mice have frequent epileptiform discharges. (A) Spontaneous generalized convulsive seizure, (B) spike-wave discharge (SWD) (arrows) and (C) single spike in a 10-month-old APP/PS1 mouse (arrows). The arrowheads indicate normal electroencephalogram background following single spike. (D) Quantification of SWDs in APP/PS1 mice compared with their wild-type (WT) littermates. (E) Quantification of single spikes does not show a difference between APP/PS1 mice and WT littermates (n = 8 for WT, 19 for APP/PS1). *P < 0.05 by Student’s t-test. WT, five females and three males; APP/PS1 mice with SWDs, four males and five females; APP/PS1 mice without SWDs, six females and four males. Calibration: SWD = 200 μV/0.5 s; spike = 200 μV/1 s.
Mentions: Recently, authors have reported various types of epileptiform discharges in transgenic AD mice overexpressing APP. In the J20 model (APPswe,Ind), both generalized seizures and single spikes were reported [4], and APP/PS1 mice were found to have single spikes, clusters of SWDs and generalized seizures, when compared with nontransgenic littermate controls [5,18]. We have previously shown that 40% of aged APP/PS1 mice have convulsive seizures when recorded for 72 hours by continuous EEG video monitoring (Figure 1A) [6]. To further characterize epileptiform activity in transgenic AD mice, we assessed nineteen 8- to 10-month-old APP/PS1 mice using long-term in vivo EEG video monitoring. In addition to convulsive seizures, 9 (47%) of 19 APP/PS1 mice had frequent clusters of SWDs, compared with 0 of 8 of their wild-type littermates (Figure 1B,D). Using synchronized video analysis, a total of 240 hours of EEG were analyzed, and freezing behavior during the SWDs that might interfere with memory testing was quantified. Overall, only 82 SWDs were associated with brief behavioral arrest for the duration of the SWD, for a rate of less than one arrest per hour. In contrast with previous authors, we show that the frequency of single spikes is not transgene-dependent and that APP/PS1 mice do not differ from their wild-type littermates (Figure 1C,E). To assess EEG characteristics in a second AD mouse model, a limited cohort of ten 3xTg-AD mice aged 8 to 10 months underwent continuous in vivo EEG recording for 24 hours as described for APP/PS1 mice. None of the 3xTg-AD mice had convulsive seizures during the recording period. Four (40%) of ten of the 3xTg-AD mice had SWDs over a 12-hour period (11 ± 6 SWDs/hr). On the basis of EEG morphology, no differences in SWDs were observed between mouse strains, and the frequency of SWDs was not found to be significantly different between the two mouse models (APP/PS1 mean: 5 ± 1 SWDs/hr versus 3xTg-AD mean: 11 ± 6 SWDs/hr; P = 0.2 by Student’s t-test). Owing to the high frequency and concordance between transgenic lines, we focused on SWDs as the primary manifestation of epileptiform activity.Figure 1

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