Aerobic Exercise Induces Alternative Splicing of Neurexins in Frontal Cortex

Abstract

Aerobic exercise (AE) is known to produce beneficial effects on brain health by improving plasticity, connectivity, and cognitive functions, but the underlying molecular mechanisms are still limited. Neurexins (Nrxns) are a family of presynaptic cell adhesion molecules that are important in synapsis formation and maturation. In vertebrates, three-neurexin genes (NRXN1, NRXN2, and NRXN3) have been identified, each encoding for α and β neurexins, from two independent promoters. Moreover, each Nrxns gene (1–3) has several alternative exons and produces many splice variants that bind to a large variety of postsynaptic ligands, playing a role in trans-synaptic specification, strength, and plasticity. In this study, we investigated the impact of a continuous progressive (CP) AE program on alternative splicing (AS) of Nrxns on two brain regions: frontal cortex (FC) and hippocampus. We showed that exercise promoted Nrxns1–3 AS at splice site 4 (SS4) both in α and β isoforms, inducing a switch from exon-excluded isoforms (SS4−) to exon-included isoforms (SS4+) in FC but not in hippocampus. Additionally, we showed that the same AE program enhanced the expression level of other genes correlated with synaptic function and plasticity only in FC. Altogether, our findings demonstrated the positive effect of CP AE on FC in inducing molecular changes underlying synaptic plasticity and suggested that FC is possibly a more sensitive structure than hippocampus to show molecular changes.

Neurexins and their ligands at inhibitory synapses

“…Changes in Nrxn mRNA expression and alternative splicing are observed following in-vivo drug administration in nucleus accumbens ( Fuccillo et al, 2015 ) and globus pallidus ( Kelai et al, 2008 ). Modifications to the inclusion of SS4 are commonly observed in multiple brain regions following several experiences, including fear conditioning ( Rozic et al, 2011 ; Ding et al, 2017 ), stress ( Freire-Cobo and Wang, 2020 ), and exercise ( Innocenzi et al, 2021 ). In studies that distinguished multiple cell-types or brain regions, Nrxn expression profiles displayed cell-type and/or region-specific changes, suggesting that Nrxn expression profiles change in accordance with circuit-specific plasticity.…”

Endurance effort affected expression the Actinin 3 and Klotho different isoforms in Arabian horses

“…Recent studies have shown that alternative splicing can be understood as an evolutionary adaptation to factors occurring an individual's life [1]. Moreover, a study by Innocenzi et al (2021) [2] based on transcriptome analyses, con rmed the occurrence of alternative splicing induced by an aerobic exercise in mice model. In humans, it has been shown that physical exercise can modify different isoforms of the genes encoding proteins crucial for skeletal muscle contraction [3].…”