Loss of serum response factor in mature neurons in the dentate gyrus alters the morphology of dendritic spines and hippocampus-dependent behavioral tasks

Abstract

Serum response factor (SRF) is a major transcription factor that regulates the expression of several plasticity-associated genes in the brain. Although the developmental expression of SRF in excitatory neurons is crucial for establishing proper hippocampal circuitry, no substantial evidence of its role in unstimulated mature neurons has been provided. The present study used time-controlled, conditional SRF knockout mice and found that the lack of SRF in adult neurons led to decreased actin levels and inactivation of the actin-severing protein cofilin 1 through its increase in phosphorylation at Ser3. The augmentation of cofilin 1 phosphorylation correlated with an alteration of dendritic spine morphology in the dentate gyrus, which was reflected by an increase in the number of spines that clustered into the long-spine category. The changes in spine morphology coincided with a lower amplitude and frequency of miniature excitatory postsynaptic currents. Moreover, SRF knockout animals were hyperactive and exhibited impairments in hippocampus-dependent behaviors, such as digging, marble burying, and nesting. Altogether, our data indicate that the adult deletion of neuronal SRF leads to alterations of spine morphology and function and hippocampus-dependent behaviors. Thus, SRF deletion in adult neurons recapitulates some aspects of morphological, electrophysiological, and behavioral changes that are observed in such psychiatric disorders as schizophrenia and autism spectrum disorders.

Serum response factor is essential for synaptic maturation in the hippocampus

“…8G; two-way repeated-measures ANOVA: genotype: F1,10 = 3.98, p = 0.074 genotype, time: F6,60 = 229.1, p < 0.0001; genotype × time: F6,60 = 10.76, p < 0.0001; Sidak multiple-comparison post hoc test, ns p > 0.05, ***p < 0.001). However, consistent with previous results (Nader et al, 2019), we found that SFR KO animals exhibited a hyperactive pattern of exploration of the novel environment, reflected by an increase in the number of visits to all Eco-HAB compartments in the first 12 h of the experiment (Fig. 8G).…”

“…SRF knockdown in developing hippocampal excitatory neurons resulted in an increase in the length of spines and number of immature filopodia-like protrusions, with a general lack of changes in the overall density of dendritic spines in vitro and in vivo. These changes in spine shape might be related to the decrease in β-actin levels and cofilin-1 inactivation upon SRF ablation, which was previously reported by us and others (Alberti et al, 2005;Beck et al, 2012;Nader et al, 2019;Zimprich et al, 2017). Notably, both proteins play a fundamental role in dendritic spine expansion (Bosch et al, 2014;Zimprich et al, 2017).…”

“…Altogether, these observations suggest that SRF controls gene expression programs that are critical for neuronal connectivity and information processing in the brain. In contrast to the paramount role of SRF in brain development, its removal in adult excitatory neurons does not affect gross hippocampal architecture (Kuzniewska et al, 2016;Losing et al, 2017;Nader et al, 2019). Despite advances in understanding the role of SRF in the central nervous system, the contributions of SRF to dendritic spine formation and neurodevelopmental disorders remain unresolved.…”

Forebrain-specific deficiency of the GTPase CRAG/Centaurin-γ3 leads to immature dentate gyri and hyperactivity in mice

“…SRF is highly expressed in the granular cells of the DG (32), regulates neurite outgrowth (33), and contributes to hippocampal layer and nerve fiber organization (34). These reports indicate that J o u r n a l P r e -p r o o f KO mice exhibit increased locomotor activity, as do CRAG/Centaurin-γ3 KO mice (35). Downregulation of SRF in CRAG/Centaurin-γ3 KO mice may suppress neuronal maturation and thereby induce iDG phenotypes.…”

Role of Cofilin in Alzheimer’s Disease

“…In the initial phase of remodeled spine substructures, active cofilin is delivered to the spine and cofilin subsequently forms a stable complex with F-actin in order to remain at the spine and consolidate the spinal expansion during the stabilization phase (Bosch et al, 2014). Meanwhile, cofilin-1 is inactivated through the increase in phosphorylation at Ser3 accompanied by alteration of dendritic spine morphology in the dentate gyrus (Nader et al, 2019). Active cofilin, induced by the role of dephosphorylation, binds to actin, and facilitates the conversion of the F-actin to G-actin (Bamburg and Bernstein, 2016).…”