Adult Deletion of SRF Increases Epileptogenesis and Decreases Activity-Induced Gene Expression

Abstract

Although the transcription factor serum response factor (SRF) has been suggested to play a role in activity-dependent gene expression and mediate plasticity-associated structural changes in the hippocampus, no unequivocal evidence has been provided for its role in brain pathology, such as epilepsy. A genome-wide program of activity-induced genes that are regulated by SRF also remains unknown. In the present study, we show that the inducible and conditional deletion of SRF in the adult mouse hippocampus increases the epileptic phenotype in the kainic acid model of epilepsy, reflected by more severe and frequent seizures. Moreover, we observe a robust decrease in activity-induced gene transcription in SRF knockout mice. We characterize the genetic program controlled by SRF in neurons and using functional annotation, we find that SRF target genes are associated with synaptic plasticity and epilepsy. Several of these SRF targets function as regulators of inhibitory or excitatory balance and the structural plasticity of neurons. Interestingly, mutations in those SRF targets have found to be associated with such human neuropsychiatric disorders, as autism and intellectual disability. We also identify novel direct SRF targets in hippocampus: Npas4, Gadd45g, and Zfp36. Altogether, our data indicate that proteins that are highly upregulated by neuronal stimulation, identified in the present study as SRF targets, may function as endogenous protectors against overactivation. Thus, the lack of these effector proteins in SRF knockout animals may lead to uncontrolled excitation and eventually epilepsy.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-014-9089-7) contains supplementary material, which is available to authorized users.

Treatment of intermittent hypoxia increases phosphorylated tau in the hippocampus via biological processes common to aging

“…2c, bottom; Additional file 1: Figure S1, bottom) also revealed that previous several experimental data had similar comprehensive gene expression to GSE62385 (IHT or aging) as follows: aging (18 months old vs. 3.5 months old) (GSE29075) [32], kainic acid (KA) treatment (KA-treated mice vs. Saline-treated mice) (GSE60772) [33], Dicer ablation (Dicer knock out (KO) mice vs. Ctrl) (GSE23847, GSE61937) [34, 35], and moderate glutamate excess (glutamate dehydrogenase 1 (Glud1) transgenic (Tg) mice vs. Ctrl) (GSE11419) [36, 37]. In particular, the alteration patterns of clusters A, B, C and E in these experimental models are summarized in Table 1.…”

Npas4: Linking Neuronal Activity to Memory

“…The mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K) pathways have been shown to be required for the induction of Npas4 by pharmacologically-induced LTP (long term potentiation) and LTD (long term depression), respectively, in mouse hippocampal slices [15]. A recent study showed that serum response factor (SRF) is a possible upstream regulator of Npas4, as its deletion led to a significant decrease in Npas4 expression [16]. Npas4’s promoter region contains two SRF binding sites, suggesting that SRF directly regulates Npas4 expression.…”

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

“…In a previous study, enhanced SRF occupancy at target genes was reported in the rat pilocarpine model [22]. However, so far, an impact of SRF on gene expression, seizure occurrence and histo-pathological seizure hallmarks was not investigated in the pilocarpine model.…”