Abstract
An imbalance of excitation and inhibition has been associated with the pathophysiology of epilepsy. Loss of GABAergic interneurons and/or synaptic inhibition has been shown in various epilepsy models and in human epilepsy. Despite this loss, several studies reported preserved or increased tonic GABAA receptor-mediated currents in epilepsy, raising the question of the source of the inhibitory transmitter. We used the unilateral intracortical kainate mouse model of temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) to answer this question. In our model we observed profound loss of interneurons in the sclerotic hippocampal CA1 region and dentate gyrus already 5 days after epilepsy induction. Consistent with the literature, the absence of interneurons caused no reduction of tonic inhibition of CA1 pyramidal neurons. In dentate granule cells the inhibitory currents were even increased in epileptic tissue. Intriguingly, immunostaining of brain sections from epileptic mice with antibodies against GABA revealed strong and progressive accumulation of the neurotransmitter in reactive astrocytes. Pharmacological inhibition of the astrocytic GABA transporter GAT3 did not affect tonic inhibition in the sclerotic hippocampus, suggesting that this transporter is not responsible for astrocytic GABA accumulation or release. Immunostaining further indicated that both decarboxylation of glutamate and putrescine degradation accounted for the increased GABA levels in reactive astrocytes. Together, our data provide evidence that the preserved tonic inhibitory currents in the epileptic brain are mediated by GABA overproduction and release from astrocytes. A deeper understanding of the underlying mechanisms may lead to new strategies for antiepileptic drug therapy.
Highlights
Epilepsy is a disorder of the brain characterized by recurrent unprovoked seizures that affects 1–2% of the population worldwide [1]
Loss of GABAergic interneurons, especially those containing parvalbumin (PARV), has been documented in human epilepsy and in several different experimental models of the disease, suggesting that it is critically involved in epileptogenesis
We have previously shown that the unilateral intracortical kainate injection model reliably mimics key morphological and functional features of chronic human Temporal lobe epilepsy (TLE)-hippocampal sclerosis (HS) [27]
Summary
Epilepsy is a disorder of the brain characterized by recurrent unprovoked seizures that affects 1–2% of the population worldwide [1]. Most recent work suggested that the compensation is accomplished by channel-mediated tonic GABA release from reactive astrocytes [21], a mechanism that was proposed to be relevant in other neurological disorders, such as Alzheimer’s disease, Parkinson’s disease or stroke [22,23,24,25] According to this scenario, reactive astrocytes aberrantly overproduce and release GABA, which in turn inhibits neuronal excitability and network activity through activation of high affinity, slowly desensitizing extrasynaptic GABAA receptors (GABAARs) [20]. Reactive astrocytes aberrantly overproduce and release GABA, which in turn inhibits neuronal excitability and network activity through activation of high affinity, slowly desensitizing extrasynaptic GABAA receptors (GABAARs) [20] In line with this view, evidence from animal models indicate that despite the loss of synaptic inhibition, tonic GABAAR-mediated currents (often termed “tonic inhibition”) are preserved or even increased in focal epilepsy [18, 20, 21]. It was suggested that reactive astrocytes suppress network excitability and prevent seizure generation through tonic GABA release, a pathway that could provide an attractive target for the development of new AEDs
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