Mtss1L Mediates Improvement in Synaptic Function Resulting from Exercise

Exercise is known to improve cognitive function, and researchers here delve into one of the mechanisms that may be responsible for this effect. Specifically, this work relates to synaptic plasticity in the brain, the ability of neurons to restructure their connections. This is important for learning and memory function. The work here is not the only project to have picked out specific genes and proteins relating to the regulation of brain function. It remains to be seen whether this can lead to some form of enhancement therapy at the end of the day, as may be the case for klotho and its effects on cognitive function.

The beneficial cognitive effects of physical exercise cross the lifespan as well as disease boundaries. Exercise alters neural activity in local hippocampal circuits, presumably by enhancing learning and memory through short and long-term changes in synaptic plasticity. The dentate gyrus is uniquely important in learning and memory, acting as an input stage for encoding contextual and spatial information from multiple brain regions. This circuit is well suited to its biological function because of its sparse coding design, with only a few dentate granule cells active at any one time. These properties also provide an ideal network to investigate how exercise-induced changes in activity-dependent gene expression affect hippocampal structural and synaptic plasticity in vivo.

While exercise is a potent enhancer of learning and memory, we know little of the underlying mechanisms that likely include alterations in synaptic efficacy in the hippocampus. To address this issue, we exposed mice to a single episode of voluntary exercise, and permanently marked activated mature hippocampal dentate granule cells using conditional Fos-TRAP mice. Exercise-activated neurons (Fos-TRAPed) showed an input-selective increase in dendritic spines and excitatory postsynaptic currents at 3 days post-exercise, indicative of exercise-induced structural plasticity.

Laser-capture microdissection and RNASeq of activated neurons revealed that the most highly induced transcript was Mtss1L, a little-studied I-BAR domain-containing gene, which we hypothesized could be involved in membrane curvature and dendritic spine formation. shRNA-mediated Mtss1L knockdown in vivo prevented the exercise-induced increases in spines and excitatory postsynaptic currents. Our results link short-term effects of exercise to activity-dependent expression of Mtss1L, which we propose as a novel effector of activity-dependent rearrangement of synapses.

Link: https://doi.org/10.7554/eLife.45920

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