The beneficial cognitive effects of physical exercise cross the lifespan as well as disease boundaries (Mandolesi et al., 2018; Saraulli et al., 2017). Exercise alters neural activity in local hippocampal circuits, presumably by enhancing learning and memory through short- and long-term changes in synaptic plasticity (Vivar et al., 2013; Voss et al., 2013). 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 (Jung and McNaughton, 1993; Leutgeb et al., 2007; Severa et al., 2017). 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.

Most studies have focused on the cognitive effects of sustained exercise (Bolz et al., 2015; Creer et al., 2010; Uda et al., 2006). However, memory improvements are well documented after acute bouts of exercise (Mandolesi et al., 2018; Perini et al., 2016). Thus, the response to a single episode of exercise may be better suited to uncover cellular and molecular cascades that form and rearrange synapses, and which evolve over minutes to weeks following exercise. We reasoned that these mechanisms could be unmasked by a single period of voluntary exercise in vivo, followed by functional and molecular analysis of subsequent changes specific to neurons that were activated during the exercise.

cFos^creERT2 transgenic mice (Fos-TRAP) provide valid proxies of neural activity (12 and Figure 1—figure supplement 1) and a means to permanently label activated dentate granule cells. During a two-hour exposure to running wheels, mice ran approximately 3 km. We examined activated cells 3 days post-running in Fos-TRAP mice crossed with a TdT reporter line (Figure 1A). We used Fos immunohistochemistry at 1 hr post-exercise, confirming robust stimulation of neuronal activity in mature granule cells (Figure 1B). The increase in Fos expression, assessed by immunohistochemistry, matched the increase in TdTomato-positive cells (TdT⁺) measured 3 or 7 day later in Fos-TRAP mice, indicating that activated granule cells were accurately and permanently labeled during the 2 hr time window Figure 1C). We refer to these cells as ‘exercise-TRAPed’. To investigate whether a single bout of exercise activated a specific subset of granule cells, we exercise TRAPed dentate granule cells (TdT⁺) and compared this population to an ensemble activated by a subsequent re-exposure to exercise either 1 or 4 days later, as measured by Fos immunohistochemistry at 2 hr after the 2nd exercise period (Figure 1D). When the two exercise periods were separated by 24 hr, only 13% of exercise TRAPed cells were activated in the 2nd exercise period. There was almost no overlap between the two neuronal ensembles (1%) when the two periods were separated by 4 days (Figure 1D, right panel). Exercise-TRAPed neurons were distributed through the granule cell body layer, without labeling in the subgranular zone. This indicates that our exercise protocol activated stochastic, non-overlapping sets of mature granule cells, consistent with the sparse coding design of this circuit.

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Higher cortical information converges on the dentate gyrus through laminated perforant path axons from the entorhinal cortex. To examine whether a single exposure to exercise altered structural plasticity in exercise-activated neurons, we analyzed exercise-TRAPed cells in mice 3 or 7 days post-exercise as compared to homecage controls (Figure 2A, left panels). Exercise-TRAPed cells showed a nearly 50% increase in dendritic spines at 3 days. This increase was limited to the outer molecular layer (OML), which interestingly, receives contextual and time information via the lateral perforant path (Hargreaves et al., 2005; Yoganarasimha et al., 2011), whereas there was no change in dendritic spines in the middle molecular layer (MML), which receives spatial information via the medial perforant path (Hafting et al., 2005; Sargolini et al., 2006). Consistent with a transient response to a single stimulus, spine density in the OML returned to baseline levels by 7 days (Figure 2A, right panels). Exercise did not affect total dendritic length in OML or MML indicating that the increase in spine density reflected an increase in the number of synapses (Figure 2—figure supplement 1).

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The increase in spine density in the OML was associated with a corresponding increase in functional synaptic input in exercise-TRAPed cells (Figure 2B). Three days after exercise, we used acute brain slices to make simultaneous whole-cell voltage clamp recordings from an exercise-TRAPed granule cell (yellow, Figure 2B, middle) and a neighboring control granule cell (green, Figure 2B, middle). Selective stimulation of lateral perforant path (LPP) axons evoked nearly three-fold larger EPSCs in the exercise-TRAPed cell of the simultaneously recorded cell pair (Figure 2C,D), whereas EPSC amplitudes evoked by stimulation of medial perforant path axons (MPP) were unaffected (Figure 2C,D). Plotting each cell pair as a function of the site of stimulation indicated that MPP cell pairs were on the unity line, whereas LPP cell pairs were below the unity line, indicative of the increased EPSCs in exercise-TRAPed cells (Figure 2E). The increased EPSC amplitudes could not be attributed to differences in intrinsic membrane properties or presynaptic release probability (Figure 2—figure supplement 2 and Supplementary file 1). These results indicate that dentate granule cells activated by a single bout of exercise show a laminar-specific increase in dendritic spines and in excitatory postsynaptic currents.

Activity-dependent gene expression is one of the main drivers of short- and long-term changes in synaptic function (West and Greenberg, 2011). To identify exercise-activated genes underlying the observed structural plasticity in the dentate gyrus, we isolated RNA from RFP⁺ nuclei of exercise-TRAPed cells (Figure 3A,B) using laser microdissection. An ensemble of 150 individual exercise-TRAPed or adjacent non-activated (RFP^-) mature granule cells was excised per mouse at 3 and 7 days post-exercise. Analysis of transcripts by RNASeq (Figure 3—figure supplement 1) revealed up- and down-regulated transcripts (Figure 3C, left panel, Supplementary file 2 and 3) of which approximately 150 transcripts were significantly upregulated in exercise-TRAPed neurons 3 days after exercise. Gene Ontology analysis indicated that most of the upregulated transcripts had signaling or synaptic functions. The top ten upregulated genes (Figure 3C) included several known genes involved in hippocampal function, such as the neuron-specific RNA-binding protein Elavl4 and the immediate early gene Egr1 (Akamatsu et al., 2005; Jones et al., 2001). Consistent with the transient increase in dendritic spines, no transcript identified at 3 days post- exercise remained elevated at 7 days (Figure 3—figure supplement 2).

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We focused on Mtss1-like (metastasis-suppressor 1-like, Mtss1L), a protein that has been little studied in the adult nervous system (Saarikangas et al., 2008). Mtss1L, (recently renamed to Mtss2, MTSSI-BAR domain containing 2) the most enriched transcript in our experiments, was nine-fold elevated compared to non-activated neighboring cells, as validated in exercise TRAPed cells by RT-PCR (Figure 3D, Figure 3—figure supplement 2). As a control for the object novelty of the running wheel, we exposed Fos-TRAP mice for 2 hr to an identical wheel that was locked, so that the mice could explore but not run. At 3 days post-exposure, there was a small increase above baseline in the number of Fos-TRAPed cells and Mtss1L expression (Figure 3—figure supplement 3), but substantially less than exercise-TRAPed mice.

To determine the spatiotemporal pattern of Mtss1L expression, we derived KOMP Mtss1L reporter mice (Skarnes et al., 2011) in which the endogenous Mtss1L promoter drives bacterial beta-galactosidase (lacZ) gene expression. LacZ expression was undetectable in the dentate gyrus of KOMP Mtss1L^+/- housed in their homecage, suggesting no expression of Mtss1L under baseline conditions. In contrast, exercise-induced LacZ expression peaked at 3 days post-exercise (Figure 4), confirming the activity-dependence of Mtss1L expression in the dentate gyrus. Mtss1L belongs to the BAR (Bin, Amphiphysin and Rvs, I-BAR) protein family, a class of proteins that function by promoting curvature in membranes. BAR domain proteins such as amphyphysin promote inward curvatures including invaginations that are involved in endocytosis or synaptic vesicles at presynaptic nerve terminals (Dawson et al., 2006). In contrast, I-BAR proteins promote outward structures typically seen in membrane protrusions. Thus, we hypothesized that Mtss1L expression-mediated exercise-dependent formation or rearrangement of synapses in postsynaptic dendrites.

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As proof of principle, we first examined the localization of endogenous Mtss1L in hippocampal neurons in vitro following exposure to brain-derived neurotrophic factor (BDNF), which is upregulated by exercise and involved in activity-dependent synaptic plasticity (Vaynman et al., 2004; Wrann et al., 2013). Mtss1L immunoreactivity was detectable only after BDNF treatment (Figure 5A), consistent with the activity-dependent expression pattern we observed in vivo.

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Mtss1L colocalized with the somatodendritic marker MAP2 along dendrites and in dendritic spines (Figure 5A). To determine whether Mtss1L could induce spine-like protrusions, we compared spine density in cultured hippocampal neurons transfected with mCherry or mCherry-Mtss1L. At DIV 14, Mtss1L overexpression markedly increased spine-like protrusions (Figure 5B) including filopodia and mushroom spine subtypes (Figure 5—figure supplement 1). The somatodendritic pattern of overexpressed mCherry-Mtss1L overlapped the endogenous Mtss1L expression (Figure 5B, yellow). mCherry-Mtss1L-expressing dendritic spines also were labeled with co-transfected PSD-95-FingR-GFP, (Fibronectin Intrabody generated with mRNA display) that binds to endogenous PSD-95 (Gross et al., 2013). PSD-95 intrabody labeling of excitatory synapses in living neurons indicated that the protrusions induced by Mtss1L also contain postsynaptic proteins (Figure 5C). In vivo, overexpression of mCherry- Mtss1lL by DNA electroporation at P0 increased spine density of mature dentate granule cells at P21 (Figure 5D). These results indicate that Mtss1L is expressed in dendrites and can induce spine-like protrusions, consistent with a putative role in synaptic plasticity.

To determine whether Mtss1L was responsible for the increase in synapses in exercise-TRAPed cells, we used a lentivirus expressing shRNAs targeting Mtss1L. Validating the efficacy of the shRNAs, shMtss1L reduced mCherry-Mtss1L mRNA and protein expression in HEK293T cells and in primary hippocampal neurons treated with BDNF (Figure 6—figure supplement 1). To knockdown Mtss1L in vivo (Figure 6A), a combination of two lentiviral shMtss1L-GFP constructs or a shscramble-GFP were injected into the dentate gyrus of Fos-TRAP mice. Three weeks post-viral injection, we assessed spine density and excitatory synaptic function in TdT⁺ (exercise-TRAPed) granule cells that also co-expressed GFP as a marker for shRNA expression. At 3 days post-exercise, knockdown of Mtss1L occluded the exercise-induced increase in dendritic spines in the OML (Figure 6B middle panel top, and right panel). The shscramble-GFP, injected into the contralateral dentate gyrus of the same mice, had no effect (Figure 6B right panel). Viral knockdown of Mtss1L in exercise-TRAPed cells also prevented the increase in evoked EPSCs in simultaneous paired recordings from TdT^- and TdT⁺/GFP⁺ granule cells (Figure 6C–D). The amplitude of EPSCs following viral knockdown in exercise-TRAPed cells was the same as neighboring cells that were not activated by exercise (Figure 6D, right panel). Intrinsic membrane properties were not affected by Mtss1L knockdown (Supplementary file 1). Figure 6E includes the results from Figure 2 (‘exercise-TRAPed OML’ (red) and ‘exercise-TRAPED MML’ (black), compared to the effects of Mtss1L shRNA (yellow), demonstrating that knockdown of Mtss1L was necessary to explain the exercise-induced increase in excitatory synapses. Importantly, evoked EPSCs in granule cells that only expressed GFP +shRNA were unaffected, demonstrating that the effect of Mtss1L was dependent on activity-dependent expression (Figure 6—figure supplement 2).

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Our experiments were designed to test the cellular and molecular response to acute exercise with an emphasis on time periods during which synapses might form or reorganize. This approach differs from studies of sustained or chronic exercise that likely involve systemic as well as neural mechanisms (Vivar et al., 2013; Voss et al., 2013; van Praag and Christie, 2015). Such studies have shown effects of exercise on many aspects of hippocampal function, including neurogenesis, synaptic plasticity, structural changes at synapses and dendritic spines as well as behavioral effects on learning and memory (Mandolesi et al., 2018; Saraulli et al., 2017). Our goal was to examine the transcriptional response in the days following acute exercise, which led to the identification of a novel effector of structural plasticity, Mtss1L.

Although the Fos-TRAP method is limited by the time required for reporter expression (ca. 1 day post-exercise), the immediate early gene Egr1 was upregulated (Figure 3C), indicating that our protocol detected activity-dependent gene expression in mature granule cells. Although introduction of the running wheel for 2 hr itself could act as a novel object, there was a small increase in Fos-TRAPed cells when the wheel was fixed to prevent running. These results indicate that exercise is a particularly strong stimulus for activation of granule cells, but as expected other stimuli can also activate dentate granule cells (Ryan et al., 2015). Adult-generated granule cells in the subgranular zone were not activated by 2 hr of exercise (data not shown). Although it is well known that chronic exercise increases adult neurogenesis (van Praag, 2008), progenitors and newborn neurons do not receive direct excitatory perforant path input for several weeks (Overstreet et al., 2004), perhaps explaining their lack of activation in our experiments.

Our results provide the first evidence for activity-dependent expression of an I-BAR protein as well as a role in experience-dependent remodeling of synapses. However, I-BAR proteins including MIM (Mtss1L) and IRSp53 can affect constitutive dendritic spine formation (Saarikangas et al., 2015; Choi et al., 2005). For example, MIM/Mtss1, is involved in cerebellar synapse formation via PIP2-dependent membrane curvature and subsequent Arp2/3-mediated action polymerization (Saarikangas et al., 2015). Expression of Mtss1L in neurons has gone largely undetected, likely a result of the previously unrecognized activity-dependence. However, Mtss1L has been detected in radial glial cells during development and implicated in glial membrane protrusions and end-feet (Saarikangas et al., 2008). I-BAR protein function at synapses is thought to be mediated by several interaction domains including the N-terminal I-BAR domain and a C-terminal actin-monomer-binding WH2 domain (Zhao et al., 2011), and may depend on slice variants. For example, the effects of MIM in cerebellar neurons is splice-variant specific (Sistig et al., 2017). Mtss1L also has two known splice variants, both of which were targeted in our overexpression and knockdown experiments. It will be interesting to investigate how protein-protein interactions and splice variants of Mtss1L contribute to their role in synaptic remodeling.

At a circuit level, the laminar-specific increase in synaptic function suggests that acute exercise had a network-specific effect. Entorhinal inputs to the outer molecular layer, the distal dendrites of mature granule cells, have been previously associated with contextual information and particularly the ‘how’ and ‘when’ aspects of encoding memories (Tsao et al., 2018). How might these results relate to the beneficial effects of exercise? One possibility consistent with our data is that exercise acts as a preconditioning signal that primes exercise-activated neurons for contextual information incoming during the several days following exercise. This represents a broader time window than is usually associated with short-term plasticity. For example, human studies give support for the idea that exercise within 4 hr of a learning task improved memory performance (van Dongen et al., 2016). It will be interesting to examine if exercise enhances the pattern of granule cell responses to spatial or context-specific tasks. Our identification of Mtss1L as an activity-dependent I-BAR domain protein makes it ideally suited to act as an early mediator of structural plasticity following neural activity.

RNA seq data generated in the manuscript have been deposited at https://www.ncbi.nlm.nih.gov/bioproject/PRJNA481775.

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Author details

1. Christina Chatzi

   Vollum Institute, Oregon Health & Science University, Portland, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing

   Contributed equally with

   Yingyu Zhang

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8922-5617

2. Yingyu Zhang

   Vollum Institute, Oregon Health & Science University, Portland, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Validation, Investigation, Visualization, Methodology, Writing—review and editing

   Contributed equally with

   Christina Chatzi

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3414-4059

3. Wiiliam D Hendricks

   1. Vollum Institute, Oregon Health & Science University, Portland, United States
   2. Neuroscience Graduate Program, Vollum Institute, Oregon Health & Science University, Portland, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2841-577X

4. Yang Chen

   1. Vollum Institute, Oregon Health & Science University, Portland, United States
   2. Neuroscience Graduate Program, Vollum Institute, Oregon Health & Science University, Portland, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4365-9900

5. Eric Schnell

   1. Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, United States
   2. Portland VA Health Care System, Portland, United States

   Contribution

   Conceptualization, Resources, Data curation, Software, Supervision, Funding acquisition, Validation, Investigation, Visualization, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5623-5015

6. Richard H Goodman

   Vollum Institute, Oregon Health & Science University, Portland, United States

   Contribution

   Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

7. Gary L Westbrook

   Vollum Institute, Oregon Health & Science University, Portland, United States

   Contribution

   Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   westbroo@ohsu.edu

   Competing interests

   Senior editor, eLife

   "This ORCID iD identifies the author of this article:" 0000-0002-8108-5223

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