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

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 (Srf CaMKCreERT2) 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-017-0310-2) contains supplementary material, which is available to authorized users.

Interference of neuronal activity‐mediated gene expression through serum response factor deletion enhances mortality and hyperactivity after traumatic brain injury

“…In this study, previously described neuron specific Srf mutant mice were used. 33,34,44 We used male and female offspring derived from breeding pairs of parental mice harboring the CreERT2 allele and one "floxed" and one wild-type Srf allele (for more details see "Experimental details," below). To induce a neuron specific deletion of Srf, CreERT2 positive mice with two "floxed" Srf alleles were daily ip injected with tamoxifen (2 mg dissolved in 10% ethanol in peanut oil, Sigma) for 5 consecutive days.…”

“…37,52 In contrast, during LTP and seizure propagation cFos was regulated in an SRF-dependent manner. 34,38,39 Thus, cFos and family members appear as facultative SRF target genes and other TFs such as CREB might have a stronger impact. 60 In contrast, Egr1, Egr2, Egr3, and also Npas4 appear to be more constitutively SRF dependent for a wide range of in vivo stimuli.…”

“…60 In contrast, Egr1, Egr2, Egr3, and also Npas4 appear to be more constitutively SRF dependent for a wide range of in vivo stimuli. 34,52 How might SRF-dependent gene expression during TBI be connected to the hyperactivity phenotype observed in Srf mutant mice? In one possible scenario, TBI results in an immediate increase in neuronal activity in wt brains.…”

“…[28][29][30][31][32] However, a functional role of SRF or one of these IEGs in TBI has not been described. In this study we employ neuron restricted SRF deletion in mice 33,34 to show a first SRF function in a rodent TBI model. 35,36 In previous reports, such SRF deficient mice revealed impaired stress responsiveness, 33 a hyperactivity and decreased anxiety phenotype, 33,37 altered seizure propagation 34,38 and impaired long-term potentiation 39 and depression.…”

“…In this study we employ neuron restricted SRF deletion in mice 33,34 to show a first SRF function in a rodent TBI model. 35,36 In previous reports, such SRF deficient mice revealed impaired stress responsiveness, 33 a hyperactivity and decreased anxiety phenotype, 33,37 altered seizure propagation 34,38 and impaired long-term potentiation 39 and depression. 40 For instance, challenging mice with a novel environment, 39 acute stress, 33 electroconvulsive shocks, 39 or epileptic seizures 34,41 upregulates IEGs in wildtype (wt) mice whereas this was strongly diminished for several IEGs after SRF ablation.…”