Maternal Methyl-Enriched Diet Increases DNMT1, HCN1, and TH Gene Expression and Suppresses Absence Seizures and Comorbid Depression in Offspring of WAG/Rij Rats

Sarkisova, K. Yu.; Fedosova, Ekaterina; Shatskova, Alla; Rudenok, Margarita M.; Stanishevskaya, Vera A.; Slominsky, Petr

doi:10.3390/diagnostics13030398

Cited by 8 publications

(8 citation statements)

References 53 publications

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“…Although few studies have examined the effects of MCS on hyperexcitability, our results showing the benefits of high choline are consistent with reports that a methyl-enriched diet (including choline but also betaine, folic acid, vitamin B12, l -methionine, and zinc) reduced spike wave discharges ( Sarkisova et al, 2023 ) and audiogenic seizure severity ( Poletaeva et al, 2014 ) in the offspring. Also, perinatal ethanol treatment that increased excitability was mitigated by choline chloride injection from postnatal days 10–30 ( Grafe et al, 2022 ).…”

Section: Discussionsupporting

confidence: 91%

Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer’s disease

Chartampila,

Elayouby,

Leary

et al. 2024

eLife

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Maternal choline supplementation (MCS) improves cognition in Alzheimer’s disease (AD) models. However, effects of MCS on neuronal hyperexcitability in AD are unknown. We investigated effects of MCS in a well-established mouse model of AD with hyperexcitability, the Tg2576 mouse. The most common type of hyperexcitability in Tg2576 mice, and many other mouse models and AD patients, are generalized EEG spikes (interictal spikes; IIS). Hyperexcitability is also reflected by elevated expression of the transcription factor ΔFosB in the principal cells of the dentate gyrus (DG), granule cells (GCs). We also studied the hilus of the DG because hilar neurons regulate GC excitability. We found reduced expression of the neuronal marker NeuN within hilar neurons in Tg2576 mice, which other studies have shown is a sign of oxidative stress or other pathology.Tg2576 breeding pairs received a diet with a relatively low, intermediate or high concentration of choline. After weaning, all mice received the intermediate diet. In offspring of mice fed the high choline diet, IIS frequency declined, GC ΔFosB expression was reduced, and NeuN expression restored. Spatial memory improved. In contrast, offspring exposed to the relatively low choline diet had several adverse effects, such as increased mortality. The results provide new evidence that a diet high in choline in early life can improve outcomes in a mouse model of AD, and relatively low choline can have negative consequences. This is the first study showing that dietary choline can regulate hyperexcitability, hilar neurons, and spatial memory in an animal model of AD.

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Section: Discussionsupporting

confidence: 91%

Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer’s disease

Chartampila,

Elayouby,

Leary

et al. 2024

eLife

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show abstract

“…Although few studies have examined the effects of MCS on hyperexcitability, our results showing the benefits of high choline are consistent with reports that a methyl-enriched diet (including choline but also betaine, folic acid, vitamin B12, L-methionine and zinc) reduced spike wave discharges in the offspring (Sarkisova et al, 2023) and audiogenic seizure severity (Poletaeva et al, 2014).…”

Section: Benefits Of High Cholinesupporting

confidence: 91%

Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer’s disease

Chartampila

Elayouby

Leary

et al. 2023

Preprint

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Maternal choline supplementation (MCS) improves cognition in Alzheimer's disease (AD). However, the effects of MCS on neuronal hyperexcitability in AD are unknown. Therefore, we investigated the effects of MCS in a well-established mouse model of AD, the Tg2576 mouse. Like many AD mouse models and patients, Tg2576 mice exhibit hyperexcitability, typically generalized EEG spikes (interictal spikes; IIS). Hyperexcitability is also reflected by elevated expression of the transcription factor deltaFosB in the principal cells of the dentate gyrus (DG), granule cells (GCs). We also studied the hilus of the DG because hilar neurons regulate GC excitability. We found that hilar neurons reduce expression of the neuronal marker NeuN in Tg2576 mice, which other studies have shown is a sign of oxidative stress or pathology. Tg2576 breeding pairs received a diet with a relatively low, intermediate or high concentration of choline. After weaning, all mice received the intermediate diet. In offspring of mice fed the high choline diet, IIS frequency declined, GC deltaFosB expression was reduced, and NeuN expression restored. Spatial memory improved. In contrast, offspring of mice fed the relatively low choline diet had several adverse effects, such as increased mortality, suggesting poor health. The results provide new evidence that a diet high in choline in early life can improve outcomes in a mouse model of AD, and relatively low choline can have negative consequences. This is the first study showing that dietary choline can regulate hyperexcitability, hilar neurons, and spatial memory in an animal model of AD.

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“…These data indicate that treatment with methyl-group donors during neurodevelopment, which is the most sensitive period for epigenetic modifications, can exert long-lasting disease-modifying effects and, therefore, may represent a promising new approach to the treatment of depressive disorders related or unrelated to seizures. Here we have shown that short-term treatment of adult WAG/Rij rats with a methyl-group donor can be as effective in alleviating depression and associated absence seizures as early and long-term treatment [20]. The question of whether L-MET treatment causes a change in the expression of genes, including those related to the metabolism of monoamines in the brain, as well as what their epigenetic mechanisms are, awaits further research.…”

Section: Discussionmentioning

confidence: 87%

“…In our previous work, a maternal diet enriched with methyl-group donors and cofactors of the one-carbon cycle (choline, betaine, folic acid, vitamin B12, L-MET, zinc) during the perinatal period enhanced the DAergic tone of the brain mesolimbic system [72], increased the expression of selected genes potentially representing the cause of the pathology, and suppressed the occurrence of absence seizures and comorbid depression in adult offspring of the WAG/Rij rats [20]. SAMe treatment of pregnant submissive mice, as a model of depression, alleviated depressive-like behavioral symptoms and changed the level of brain monoamines and the expression of genes related to monoamine metabolism in adult offspring [73].…”

Section: Discussionmentioning

confidence: 94%

“…Although a pathologic phenotype in WAG/Rij rats is genetically determined, previous data have shown that the absence epilepsy and depression-like comorbidity can be altered by early postnatal environmental impacts (maternal care, maternal diet, neonatal maternal separation, and neonatal handling), indicating that epigenetic mechanisms might be involved [13,20].…”

Section: Introductionmentioning

confidence: 99%

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Antidepressant and Anxiolytic Effects of L-Methionine in the WAG/Rij Rat Model of Depression Comorbid with Absence Epilepsy

Sarkisova

Gabova

Fedosova

et al. 2023

IJMS

Self Cite

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Depression is a severe and widespread psychiatric disease that often accompanies epilepsy. Antidepressant treatment of depression comorbid with epilepsy is a major concern due to the risk of seizure aggravation. SAMe, a universal methyl donor for DNA methylation and the synthesis of brain monoamines, is known to have high antidepressant activity. This study aimed to find out whether L-methionine (L-MET), a precursor of SAMe, can have antidepressant and/or anxiolytic effects in the WAG/Rij rat model of depression comorbid with absence epilepsy. The results indicate that L-MET reduces the level of anxiety and depression in WAG/Rij rats and suppresses associated epileptic seizures, in contrast to conventional antidepressant imipramine, which aggravates absence seizures. The antidepressant effect of L-MET was comparable with that of the conventional antidepressants imipramine and fluoxetine. However, the antidepressant profile of L-MET was more similar to imipramine than to fluoxetine. Taken together, our findings suggest that L-MET could serve as a promising new antidepressant drug with anxiolytic properties for the treatment of depression comorbid with absence epilepsy. Increases in the level of monoamines and their metabolites—DA, DOPAC, HVA, NA, and MHPG—in several brain structures, is suggested to be a neurochemical mechanism of the beneficial phenotypic effect of L-MET.

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Maternal Methyl-Enriched Diet Increases DNMT1, HCN1, and TH Gene Expression and Suppresses Absence Seizures and Comorbid Depression in Offspring of WAG/Rij Rats

Cited by 8 publications

References 53 publications

Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer’s disease

Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer’s disease

Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer’s disease

Antidepressant and Anxiolytic Effects of L-Methionine in the WAG/Rij Rat Model of Depression Comorbid with Absence Epilepsy

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