SRF modulates seizure occurrence, activity induced gene transcription and hippocampal circuit reorganization in the mouse pilocarpine epilepsy model

Pascal Lösing,Merle Harrer,Snezana Maljevic,Christopher Meyer Zu Reckendorf,Bernd Knöll,Daniela Sinske,Theresa Schatz,Cristina Elena Niturad,Holger Lerche

doi:10.1186/s13041-017-0310-2

Abstract

A hallmark of temporal lobe epilepsy (TLE) is hippocampal neuronal demise and aberrant mossy fiber sprouting. In addition, unrestrained neuronal activity in TLE patients induces gene expression including immediate early genes (IEGs) such as Fos and Egr1.We employed the mouse pilocarpine model to analyze the transcription factor (TF) serum response factor (SRF) in epileptogenesis, seizure induced histopathology and IEG induction. SRF is a neuronal activity regulated TF stimulating IEG expression as well as nerve fiber growth and guidance. Adult conditional SRF deficient mice (SrfCaMKCreERT2) were more refractory to initial status epilepticus (SE) acquisition. Further, SRF deficient mice developed more spontaneous recurrent seizures (SRS). Genome-wide transcriptomic analysis uncovered a requirement of SRF for SE and SRS induced IEG induction (e.g. Fos, Egr1, Arc, Npas4, Btg2, Atf3). SRF was required for epilepsy associated neurodegeneration, mossy fiber sprouting and inflammation. We uncovered MAP kinase signaling as SRF target during epilepsy. Upon SRF ablation, seizure evoked induction of dual specific phosphatases (Dusp5 and Dusp6) was reduced. Lower expression of these negative ERK kinase regulators correlated with altered P-ERK levels in epileptic Srf mutant animals.Overall, this study uncovered an SRF contribution to several processes of epileptogenesis in the pilocarpine model.

Highlights

Epilepsy is characterized by repeated seizures as a result of uncontrolled neuronal network synchronization occurring in 1% of the population
We compared Srf +/+; CaMKCreERT2 and Srf loxp/+; CaMKCreERT2 mice to see whether loss of one Srf allele in heterozygous mice already has an impact on seizure occurrence and gene expression
(See figure on previous page.) Fig. 9 Activity of MAP kinase signaling members is altered upon serum response factor (SRF) ablation. a-h Hippocampal sections were labeled with anti P-ERK directed antibodies and counterstained with Nissl

Summary

Introduction

Epilepsy is characterized by repeated seizures as a result of uncontrolled neuronal network synchronization occurring in 1% of the population. Temporal lobe epilepsy (TLE) is the most common form of partial epilepsy which accounts for about 60% of partial epilepsy cases [1, 2]. TLE affected neuronal networks show several molecular and anatomical alterations [3,4,5,6]. In resected brain areas of TLE patients, excessive neuronal activity stimulates rapid neuronal gene induction including IEGs [7, 8]. Hippocampal sclerosis is a neuropathological hallmark in many patients.

Methods

Results

Conclusion