Early reduced dopaminergic tone mediated by D3 receptor and dopamine transporter in absence epileptogenesis

Abstract

Objective In Genetic Absence Epilepsy Rats From Strasbourg (GAERSs), epileptogenesis takes place during brain maturation and correlates with increased mRNA expression of D3 dopamine receptors (D3R). Whether these alterations are the consequence of seizure repetition or contribute to the development of epilepsy remains to be clarified. Here, we addressed the involvement of the dopaminergic system in epilepsy onset in GAERSs. Methods Experiments were performed using rats at different stages of brain maturation from three strains according to their increasing propensity to develop absence seizures: nonepileptic control rats (NECs), Wistar Hannover rats, and GAERSs. Changes in dopaminergic neurotransmission were investigated using different behavioral and neurochemical approaches: autoradiography of D3R and dopamine transporter, single photon emission computed tomographic imaging, acute and chronic drug effects on seizure recordings (dopaminergic agonists and antagonists), quinpirole‐induced yawns and dopamine synaptosomal uptake, microdialysis, brain tissue monoamines, and brain‐derived neurotrophic factor quantification. Results Autoradiography revealed an increased expression of D3R in 14‐day‐old GAERSs, before absence seizure onset, that persists in adulthood, as compared to age‐matched NECs. This was confirmed by increased yawns, a marker of D3R activity, and increased seizures when animals were injected with quinpirole at low doses to activate D3R. We also observed a concomitant increase in the expression and activity of the dopamine transporter in GAERSs before seizure onset, consistent with both lowered dopamine basal level and increased phasic responses. Significance Our data show that the dopaminergic system is persistently altered in GAERSs, which may contribute not only to behavioral comorbidities but also as an etiopathogenic factor in the development of epilepsy. The data suggest that an imbalanced dopaminergic tone may contribute to absence epilepsy development and seizure onset, as its reversion by a chronic treatment with a dopamine stabilizer significantly suppressed epileptogenesis. Our data suggest a potential new target for antiepileptic therapies and/or improvement of quality of life of epileptic patients.

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

“…Insufficiency of these neurotransmitter systems in the brain is known to be associated with depressive disorders. Moreover, the reduced dopaminergic tone is also implicated to be involved in absence epileptogenesis [26]. This implies that increased expression of the TH gene in the nucleus accumbens as well as increased dopaminergic tone of the mesolimbic brain system may contribute to the suppression of absence seizures and depression-like comorbidity in the offspring of WAG/Rij rats.…”

“…There is evidence that a reduced dopaminergic tone may contribute to depression-like behavioural comorbidity [20] and the genesis of SWDs [26] in genetic models of absence epilepsy. Of note, a hypofunction of the mesolimbic dopaminergic brain system, which persisted and intensified with age, was found before the absence seizure onset [26] and the appearance of comorbid depression [20].…”

“…There is evidence that a reduced dopaminergic tone may contribute to depression-like behavioural comorbidity [20] and the genesis of SWDs [26] in genetic models of absence epilepsy. Of note, a hypofunction of the mesolimbic dopaminergic brain system, which persisted and intensified with age, was found before the absence seizure onset [26] and the appearance of comorbid depression [20]. This means that targeting the expression of HCN1 ion channels in the somatosensory cortex and the mesolimbic dopaminergic system could be a potential new approach for treating absence epilepsy and comorbid depression in the WAG/Rij model.…”

The impact of early-life environment on absence epilepsy and neuropsychiatric comorbidities

“…Moreover, the absence epileptogenesis could also be associated with a reduced DAergic tone. Decreased tonic release of DA has been suggested to act as a facilitating and self-sustaining factor, which may lead to increased excitability of the somatosensory cortex ( Cavarec et al, 2019 ) and thereby contribute to the generation of SWDs. Interestingly, neurochemical alterations of the DAergic brain system begin to appear before the occurrence of SWDs in WAG/Rij rats ( Sarkisova et al, 2014 ).…”

“…Thus, these results allow us to assume that the seizure-reducing effect of neonatal tactile stimulation in WAG/Rij rats ( Balikci et al, 2020 ) can be mediated by its influence on the morphologic characteristics of dendrites in the somatosensory cortex leading to a decrease in the excitability of the epileptogenic cortical focus. It cannot be excluded that artificial neonatal tactile stimulation in WAG/Rij rats, like a natural mother’s care, might affect the development of the mesolimbic DA pathway ( Peña et al, 2014 ), which is impaired in young WAG/Rij rats ( Malyshev et al, 2014 ) and insufficiency of which is implicated both in absence epileptogenesis ( Cavarec et al, 2019 ) and in the expression of depression-like symptoms in adult WAG/Rij rats ( Sarkisova et al, 2013 ).…”