The translation initiating factor eIF4E and arginine methylation underlie G3BP1 function in dendritic spine development of neurons.

Communication between neurons relies on neurotransmission that takes place at synapses. Excitatory synapses are located primarily on dendritic spines that possess diverse morphologies, ranging from elongated filopodia to mushroom-shaped spines. Failure in the proper development of dendritic spines has detrimental consequences on neuronal connectivity, but the molecular mechanism that controls the balance of filopodia and mushroom spines is not well understood. G3BP1 is the key RNA-binding protein that assembles the stress granules in non-neuronal cells to adjust protein synthesis upon exogenous stress. Emerging evidence suggests that the biological significance of G3BP1 extends beyond its role in stress response, especially in the nervous system. However, the mechanism underlying the regulation and function of G3BP1 in neurons remains elusive. Here we found that G3BP1 suppresses protein synthesis and binds to the translation initiation factor eIF4E via its NTF2-like domain. Notably, the over-production of filopodia caused by G3BP1 depletion can be alleviated by blocking the formation of the translation initiation complex. We further found that the interaction of G3BP1 with eIF4E is regulated by arginine methylation. Knockdown of the protein arginine methyltransferase PRMT8 leads to elevated protein synthesis and filopodia production, which is reversed by the expression of methylation-mimetic G3BP1. Our study, therefore, reveals arginine methylation as a key regulatory mechanism of G3BP1 during dendritic spine morphogenesis and identifies eIF4E as a novel downstream target of G3BP1 in neuronal development independent of stress response.

Neuromodulation and hippocampal neurogenesis in depression: A scoping review.

The 'neurogenesis hypothesis of depression' emphasizes the importance of upregulated hippocampal neurogenesis for the efficacy of antidepressant treatment. Neuromodulation is a promising therapeutic method that stimulates neural circuitries to treat neuropsychiatric illnesses. We conducted a scoping review on the neurogenic and antidepressant outcomes of neuromodulation in animal models of depression. PubMed, Web of Science, and PsycInfo were comprehensively searched for full-text English articles from inception to October 5, 2021. Data screening and extraction were conducted independently by two researchers. Seventeen eligible studies were included in this review. The majority of studies used non-invasive neuromodulation (n = 14) and assessed neurogenesis using neural proliferation (n = 16) and differentiation markers (n = 9). Limited reports (n = 2) used neurogenic inhibitors to evaluate the role of neurogenesis on the depressive-like behavioral outcomes. Overall, neuromodulation substantially effectuated both hippocampal cell proliferation and antidepressant-like behavior in animal models of depression, with some providing evidence for enhanced neuronal differentiation and maturation. The proposed neurogenic-related mechanisms mediating the neuromodulation efficacies included neurotrophic processes, anti-apoptotic pathways, and normalization of HPA axis functions. Further research is warranted to explore the role of neuromodulation-induced neurogenic effects on treatment efficacies and to elucidate the underlying molecular mechanisms.