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Neuritin is a member of the neurotrophic factor family, which is activated by neural activity and neurotrophins, and promotes neurite growth and branching. It has shown to play an important role in neuronal plasticity and regeneration. It is also involved in other biological processes such as angiogenesis, tumorigenesis and immunomodulation. Thus far, however, the primary mechanisms of neuritin, including whether or not it acts through a receptor or which downstream signals might be activated following binding, are not fully understood. Recent evidence suggests that neuritin may be a potential therapeutic target in several neurodegenerative diseases. This review focuses on the recent advances in studies regarding the newly identified functions of neuritin and the signaling pathways related to these functions. We also discuss current hot topics and difficulties in neuritin research.

Neuritin is an important neurotrophin that regulates neural development, synaptic plasticity, and neuronal survival. Elucidating the downstream molecular signaling is important for potential therapeutic applications of neuritin in neuronal dysfunctions. We previously showed that neuritin up-regulates transient potassium outward current (IA) subunit Kv4.2 expression and increases IA densities, in part by activating the insulin receptor signaling pathway. Molecular mechanisms of neuritin-induced Kv4.2 expression remain elusive. Here, we report that the Ca(2+)/calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) c4 axis is required for neuritin-induced Kv4.2 transcriptional expression and potentiation of IA densities in cerebellum granule neurons. We found that neuritin elevates intracellular Ca(2+) and increases Kv4.2 expression and IA densities; this effect was sensitive to CaN inhibition and was eliminated in Nfatc4(-/-) mice but not in Nfatc2(-/-) mice. Stimulation with neuritin significantly increased nuclear accumulation of NFATc4 in cerebellum granule cells and HeLa cells, which expressed IR. Furthermore, NFATc4 was recruited to the Kv4.2 gene promoter loci detected by luciferase reporter and chromatin immunoprecipitation assays. More importantly, data obtained from cortical neurons following adeno-associated virus-mediated overexpression of neuritin indicated that reduced neuronal excitability and increased formation of dendritic spines were abrogated in the Nfatc4(-/-) mice. Together, these data demonstrate an indispensable role for the CaN/NFATc4 signaling pathway in neuritin-regulated neuronal functions.

Animal studies have shown that electromagnetic field exposure may interfere with the activity of brain cells, thereby generating behavioral and cognitive disturbances. However, the underlying mechanisms and possible preventions are still unknown. In this study, we used a mouse model to examine the effects of exposure to extremely low-frequency (50 Hz) electromagnetic fields (ELF MFs) on a recognition memory task and morphological changes of hippocampal neurons. The data showed that ELF MFs exposure (1 mT, 12 h/day) induced a time-dependent deficit in novel object associative recognition memory and also decreased hippocampal dendritic spine density. This effect was observed without corresponding changes in spontaneous locomotor activity and was transient, which has only been seen after exposing mice to ELF MFs for 7-10 days. The over-expression of hippocampal neuritin, an activity-dependent neurotrophic factor, using an adeno-associated virus (AAV) vector significantly increased the neuritin level and dendritic spine density. This increase was paralleled with ELF MFs exposure-induced deficits in recognition memory and reductions of dendritic spine density. Collectively, our study provides evidence for the association between ELF MFs exposure, impairment of recognition memory and resulting changes in hippocampal dendritic spine density. Neuritin prevented this ELF MFs-exposure-induced effect by increasing the hippocampal spine density.

Extremely low-frequency (50Hz) electromagnetic fields (ELF MFs) are ubiquitously present in various environments during daily life. The major sources of ELF MFs pertaining to the general public are in-house installations, household appliances and power lines. Animal studies have shown that ELF MFs exposure may interfere with the activity of brain cells, thereby generating behavioral and cognitive disturbances. However, the underlying mechanisms and possible preventions are still unknown. In our preliminary studies, we found that ICR mice that were exposed to ELF MFs had deficits in hippocampus-dependent recognition memory but no concurrent changes in their locomotor activity. Further experiments revealed that ELF MFs exposure reduced dendritic spine densities of hippocampal CA1 pyramidal cells. Meanwhile, there was no significant effect on dendritic spine diameter or length. Since previous work has shown that neuritin, an important neurotrophin, has the ability to increase the spine density of hippocampal pyramidal neurons, we decided to explore whether neuritin is capable of reversing ELF MFs exposure-induced decreases in dendritic spine density. To this end, adeno-associated virus serotype 9 (AAV9) vectors carrying human neuritin cDNA were produced and stereotaxically injected into the CA1 region of the mouse hippocampus (0.2µl per mouse) 7 days before exposure to ELF MFs. Two control groups were injected in hippocampus with the same volume of AAV-GFP or saline. Western blot analysis indicated that the expression of neuritin was increased by 60.2 ± 5.8% in the hippocampus. We then quantified the effects of AAV9-mediated neuritin over-expression on hippocampal dendritic spine number and subsequent recognition memory in mice of both non-ELF MFs and ELF MFs exposure groups. After a 2.5-week infection period, a significant increase in spine density was observed in the AAV-neuritin group. On the other hand, there was no significant difference in dendritic diameter or length among all three groups of mice. Additionally, after ELF MFs exposure (1mT) for 12 h/day for 10 days, the spine density of pyramidal neurons obtained from neuritin-overexpression mice was no longer reduced. Consequently, the recognition memory test of AAV-neuritin mice showed a significant increase in recognition index when compared to AAV-control mice. Collectively, our study provided evidence for the association between ELF MFs exposure, impairment of recognition memory, and resulting changes in hippocampal dendritic spine density. Furthermore, overexpression of neuritin has the ability to prevent the ELF MFs-exposure-induced effect by increasing the hippocampal spine density.