SRF depletion in early life contributes to social interaction deficits in the adulthood

Abstract

Alterations in social behavior are core symptoms of major developmental neuropsychiatric diseases such as autism spectrum disorders or schizophrenia. Hence, understanding their molecular and cellular underpinnings constitutes the major research task. Dysregulation of the global gene expression program in the developing brain leads to modifications in a number of neuronal connections, synaptic strength and shape, causing unbalanced neuronal plasticity, which may be important substrate in the pathogenesis of neurodevelopmental disorders, contributing to their clinical outcome. Serum response factor (SRF) is a major transcription factor in the brain. The behavioral influence of SRF deletion during neuronal differentiation and maturation has never been studied because previous attempts to knock-out the gene caused premature death. Herein, we generated mice that lacked SRF from early postnatal development to precisely investigate the role of SRF starting in the specific time window before maturation of excitatory synapses that are located on dendritic spine occurs. We show that the time-controlled loss of SRF in neurons alters specific aspects of social behaviors in SRF knock-out mice, and causes deficits in developmental spine maturation at both the structural and functional levels, including downregulated expression of the AMPARs subunits GluA1 and GluA2, and increases the percentage of filopodial/immature dendritic spines. In aggregate, our study uncovers the consequences of postnatal SRF elimination for spine maturation and social interactions revealing novel mechanisms underlying developmental neuropsychiatric diseases.

KIBRA regulates activity-induced AMPA receptor expression and synaptic plasticity in an age-dependent manner

“…Mice were injected with tamoxifen (Tam) or vehicle between P14-P16, a time at which CaMKII CreER T2 induction is fully functional. 52 Synaptic transmission and plasticity were evaluated between P21-P25 ( Figure 1 B). Using this system, KIBRA protein expression is substantially reduced in KIBRA cKO mice (Tam-injected Kibra Fl/Fl :CaMKIICreER T2 +) compared to WT mice (Tam-injected Kibra Fl/Fl :CaMKIICreER T2 -) ( Figures 1 C and 1D).…”

Prenatal and postnatal challenges affect the hypothalamic molecular pathways that regulate hormonal levels

“…The ablation of RORC in mice lowers inflammation in autoimmune encephalomyelitis and lowers Th17 cells in the central nervous system that promote depression-like behaviors [ 71 ]. Similarly, depletion of the enriched transcription factor SRF during early life contributes to autism-like deficits in social interaction in adulthood and neurodevelopmental disorders [ 72 ]. The enrichment of PBX1, which targets the genes Cga and Prl , can be related to findings that this transcription factor was associated with autism spectrum disorder in a transcriptome study of adult cortical tissue in humans [ 73 ].…”

Subsequent maternal sleep deprivation aggravates neurobehavioral abnormalities, inflammation, and synaptic function in adult male mice exposed to prenatal inflammation

“…Substantial evidence supports the existence of a direct link between synaptic plasticity and anxiety, depression, and cognitive function ( Wang et al, 2021 ; Hu et al, 2023 ). Early life is a critical period for synaptic pruning, synaptic maturation, and neural network establishment, and is susceptible to interference from external environmental factors ( Malave et al, 2022 ; Roszkowska et al, 2022 ). One study reported that exposure to inflammation in utero increased the levels of synaptic pruning-associated proteins (C3 and CR3A) and decreased dendrite length and dendritic spine density in offspring mice ( Xiao et al, 2021 ).…”