Serum Response Factor (SRF) Ablation Interferes with Acute Stress-Associated Immediate and Long-Term Coping Mechanisms

Abstract

Stress experience modulates behavior, metabolism, and energy expenditure of organisms. One molecular hallmark of an acute stress response is a rapid induction of immediate early genes (IEGs) such as c-Fos and Egr family members. IEG transcription in neurons is mediated by the neuronal activity-driven gene regulator serum response factor (SRF). We show a first role of SRF in immediate and long-lasting acute restraint stress (AS) responses. For this, we employed a standardized mouse phenotyping protocol at the German Mouse Clinic (GMC) including behavioral, metabolic, and cardiologic tests as well as gene expression profiling to analyze the consequences of forebrain-specific SRF deletion in mice exposed to AS. Adult mice with an SRF deletion in glutamatergic neurons (Srf; ) showed hyperactivity, decreased anxiety, and impaired working memory. In response to restraint AS, instant stress reactivity including locomotor behavior and corticosterone induction was impaired in Srf mutant mice. Interestingly, even several weeks after previous AS exposure, SRF-deficient mice showed long-lasting AS-associated changes including altered locomotion, metabolism, energy expenditure, and cardiovascular changes. This suggests a requirement of SRF for mediating long-term stress coping mechanisms in wild-type mice. SRF ablation decreased AS-mediated IEG induction and activity of the actin severing protein cofilin. In summary, our data suggest an SRF function in immediate AS reactions and long-term post-stress-associated coping mechanisms.

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

“…Others and we previously described hyperactivity, memory impairments, and decreased anxiety in Srf mutant mice including the mouse strain used in this study . Independently of these reports, experiments performed in this study confirmed hyperactivity and less anxiety in the open field (OF) test before TBI (Figure A‐F).…”

“…For this, P‐cofilin abundance––indicative of inactivated cofilin—was measured in the cerebral peduncle of sham‐ and TBI‐treated animals. In wt animals, cofilin was not phosphorylated in both sham‐ and TBI‐treated animals suggesting no obvious regulation of this actin regulator by TBI (Figure I,K,P) as also seen for acute stress exposure . In opposite to this, P‐cofilin levels were significantly upregulated upon SRF deletion ( P = .67 for wt sham vs Srf ko sham and P = .0017 for wt TBI vs Srf ko TBI; Kruskall–Wallace with DMC; Figure J,L,P).…”

“…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.…”

“…[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.…”