Abstract
ABSTRACTEpilepsy is a neurological disease that is caused by abnormal hypersynchronous activities of neuronal ensembles leading to recurrent and spontaneous seizures in human patients. Enhanced neuronal excitability and a high level of synchrony between neurons seem to trigger these spontaneous seizures. The molecular mechanisms, however, regarding the development of neuronal hyperexcitability and maintenance of epilepsy are still poorly understood. Here, we show that pumilio RNA-binding family member 2 (Pumilio2; Pum2) plays a role in the regulation of excitability in hippocampal neurons of weaned and 5-month-old male mice. Almost complete deficiency of Pum2 in adult Pum2 gene-trap mice (Pum2 GT) causes misregulation of genes involved in neuronal excitability control. Interestingly, this finding is accompanied by the development of spontaneous epileptic seizures in Pum2 GT mice. Furthermore, we detect an age-dependent increase in Scn1a (Nav1.1) and Scn8a (Nav1.6) mRNA levels together with a decrease in Scn2a (Nav1.2) transcript levels in weaned Pum2 GT that is absent in older mice. Moreover, field recordings of CA1 pyramidal neurons show a tendency towards a reduced paired-pulse inhibition after stimulation of the Schaffer-collateral-commissural pathway in Pum2 GT mice, indicating a predisposition to the development of spontaneous seizures at later stages. With the onset of spontaneous seizures at the age of 5 months, we detect increased protein levels of Nav1.1 and Nav1.2 as well as decreased protein levels of Nav1.6 in those mice. In addition, GABA receptor subunit alpha-2 (Gabra2) mRNA levels are increased in weaned and adult mice. Furthermore, we observe an enhanced GABRA2 protein level in the dendritic field of the CA1 subregion in the Pum2 GT hippocampus. We conclude that altered expression levels of known epileptic risk factors such as Nav1.1, Nav1.2, Nav1.6 and GABRA2 result in enhanced seizure susceptibility and manifestation of epilepsy in the hippocampus. Thus, our results argue for a role of Pum2 in epileptogenesis and the maintenance of epilepsy.
Highlights
Epilepsy is one of the most common neurological diseases in humans
Bioinformatic analysis of known epileptic risk factors revealed a possible Pum2-binding site in the 3′-untranslated region (3′-UTR) of Scn1a and Scn8a mRNAs. These results suggest that Pum2 is involved in the regulation of voltage-gated sodium-channel expression and thereby might control neuronal excitability in mice
MRNAs coding for Nav1.1 and Nav1.6 showed a strong upregulation in weaned Pum2 gene-trap mice (Pum2 GT) mice compared to WT
Summary
Epilepsy is one of the most common neurological diseases in humans. It is characterized by the occurrence of spontaneous seizures (Pernice et al, 2016). Voltage-gated sodium and potassium channels as well as the γ-aminobutyric acid receptor A (GABAA)-receptor family have been linked to epilepsy in animal models and human patients (Staley, 2015). It remains elusive, how those proteins act together during development and maintenance of epilepsy in adulthood
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