When part of the brain becomes damaged as a result of injury or disease – for example, a stroke – other brain regions can sometimes take over from the damaged part. This is one example of a phenomenon called brain plasticity. The strengthening and weakening of connections between neurons that underlies learning and memory is another, less extreme, example of plasticity. While the brain is most plastic during childhood, it remains malleable to some degree throughout life.

The brain’s visual system in particular shows robust and predictable plasticity, and so is often used by neuroscientists to study mechanisms behind plasticity. In young rodents, taping one eye shut for a few days causes inputs from that eye to visual areas of the brain to become weaker. Inputs from the open eye meanwhile become stronger, leading to improved vision in the open eye. Such plasticity also occurs in adult rodents, but the eye must be closed for longer to produce an effect.

In young animals, this plasticity depends, in part, on enzymes called matrix metalloproteinases (MMPs). These help to regulate a network of proteins called the extracellular matrix, which provides structural support for cells. Pielecka-Fortuna et al. now provide the first evidence that MMP enzymes also contribute to visual plasticity in adult animals. Blocking the activity of MMPs prevented reorganisation of visual areas of the brains of adult mice in response to eye closure, and prevented vision improvements in the open eye.

However, blocking MMP in adult mice whose brains had been damaged by a stroke had the opposite effect. Whereas stroke normally prevents visual system plasticity in response to eye closure, treatment with a single dose of MMP blocker rescued this plasticity. Strikingly, these benefits were lost if the mice were given two doses of MMP blocker, rather than one.

These experiments show that MMP levels must be within a narrow range to support plasticity. In the healthy adult brain, blocking MMPs impairs plasticity. After stroke, MMP levels are increased and reducing them rescues plasticity. The next challenge is to identify the specific MMP enzymes responsible, and to determine whether these changes can be exploited to improve recovery from stroke.

Neuroplasticity is the ability of the brain to adapt both structurally and functionally to changing patterns of activity induced by the environment or intrinsic factors. In the clinical setting, plasticity is important for tissue repair and neural network rewiring, necessary for recovery and optimal post-injury brain function. The primary visual cortex (V1) is a widely used model region for studying sensory plasticity in young vs. adult brains (Hofer et al., 2006; Espinosa and Stryker, 2012; Levelt and Hübener, 2012). In mammals, V1 consists of a monocular and a binocular zone; neurons in the binocular zone respond to stimulation of both eyes but are dominated by the contralateral eye in rodents (Dräger, 1975; 1978). This ocular dominance (OD) can be modified in an experience-dependent manner, by depriving one eye of pattern vision for several days (known as monocular deprivation or MD), as originally observed by Wiesel and Hubel more than 50 years ago (Wiesel and Hubel, 1965). OD-plasticity has become one of the major paradigms for studying cortical plasticity. In standard-cage raised mice, OD-plasticity in binocular V1 is most pronounced in 4-week-old animals; reduced, yet present, in early adulthood; and absent in animals older than 110 days of age (Lehmann and Löwel, 2008). In 4-week-old mice, 3-4 days of MD are sufficient to induce a significant OD-shift towards the open eye (juvenile OD-plasticity), while 7 days of MD are needed in 3-month-old animals (adult OD-plasticity) (Gordon and Stryker, 1996; Sawtell et al., 2003; Frenkel and Bear, 2004; Mrsic-Flogel et al., 2007; Sato and Stryker, 2008). Although the experimental paradigm is rather similar, molecular mechanisms underlying 'juvenile' and 'adult' OD-plasticity are different: in juvenile mice, OD-shifts are mostly mediated by reductions in deprived eye responses while adult plasticity is predominantly mediated by an increase in open eye responses in V1 (Hofer et al., 2006; Espinosa and Stryker, 2012; Levelt and Hübener, 2012).

Activity driven modifications in neuronal circuits can be facilitated by degradation of the extracellular matrix (ECM) (Pizzorusso et al., 2002; de Vivo et al., 2013), which provides structural and biochemical support for the cells (Frischknecht and Gundelfinger, 2012). Structural and molecular composition of the ECM changes during development, becoming denser and more rigid in the mature brain (Frischknecht and Gundelfinger, 2012; de Vivo et al., 2013). This structural composition is partially regulated by a family of zinc dependent endopeptidases, the matrix metalloproteinases (MMPs), and their enzymatic activity is crucial for proper development, function and maintenance of neuronal networks (Milward et al., 2007; Huntley, 2012). A recent study in juvenile rats showed that pharmacological inhibition of MMPs with a broad spectrum inhibitor during the MD-period did not influence the reduction of the closed-eye responses induced by 3 days of MD, yet it prevented the potentiation of the nondeprived eye responses in V1 after 7 days of MD (Spolidoro et al., 2012). Whether MMPs are involved in adult OD-plasticity, for which mechanisms are believed to be different (Hofer et al., 2006; Sato and Stryker, 2008; Ranson et al., 2012), is not yet known, and clarifying this point was the first goal of this study.

In addition to MMP involvement in healthy brain function, their excessive activity can also be detrimental (Agrawal et al., 2008; Huntley, 2012). Both human and animal studies found upregulated activity of MMPs following inflammation, infectious diseases or brain trauma (Agrawal et al., 2008; Rosell and Lo, 2008; Morancho et al., 2010; Vandenbroucke and Libert, 2014), and pharmacological inhibition of MMPs shortly after brain injuries reduced infarct sizes and prompted better recovery (Romanic et al., 1998; Lo et al., 2002; Gu et al., 2005; Wang and Tsirka, 2005; Yong, 2005; Morancho et al., 2010; Chang et al., 2014; Vandenbroucke and Libert, 2014). Stroke can influence synaptic activities within the area directly affected by it, and also in a broader area surrounding the lesion (Witte et al., 2000; Murphy and Corbett, 2009). Likewise, impairments in experience-dependent plasticity after a cortical stroke also have been observed in distant brain regions (Jablonka et al., 2007; Greifzu et al., 2011): in 3-month-old mice, a focal stroke in the primary somatosensory cortex (S1) prevented both V1-plasticity and improvements of the spatial frequency and contrast thresholds of the optomotor reflex of the open eye (Greifzu et al., 2011). Interestingly, some MMPs were shown to be upregulated within the first 24 hours after focal stroke (Cybulska-Klosowicz et al., 2011; Liguz-Lecznar et al., 2012). Thus, the second goal of our study was to test whether balancing the upregulated MMPs resulting from a focal stroke in S1 would rescue visual plasticity.

Using a combination of in vivo optical imaging of intrinsic signals and behavioral vision tests in adult mice, we observed that application of the broad spectrum MMP-inhibitor GM6001 during the 7-day MD-period prevented both OD-plasticity and enhancements of the optomotor response of the open eye. In addition, a single treatment after the S1-stroke rescued plasticity in both paradigms, whereas treatment with the inhibitor two times diminished plasticity-promoting effect. Together, these data reveal a crucial role of MMPs in adult visual plasticity and suggest that MMP-activity has to be within a narrow window for experience-induced plasticity to occur.

The objective of this study was to examine if MMPs are crucial for adult visual plasticity, and if inhibition of their upregulation following cortical stroke may be beneficial for rescuing lost plasticity. A combination of in vivo optical imaging and behavioral vision tests revealed that an optimal level of MMP-activity is essential for adult visual plasticity to occur in the healthy and stroke-affected brain. In healthy adult mice, MMP-inhibition with GM6001 prevented both ocular dominance plasticity and experience-driven improvements of the optomotor reflex of the open eye after MD, indicating that MMP-activation is required for normal adult plasticity. In addition, blockade of elevated MMP-activity after a cortical stroke rescued compromised plasticity. Specifically, a single but not two-times treatment with GM6001 after a cortical PT-lesion in the neighboring S1 region fully rescued experience-dependent ocular dominance plasticity in adult V1, which is normally lost under these conditions. These observations suggest that MMP-activity has to be within a narrow window to allow visual plasticity: if MMP-activity is downregulated (with inhibitors) or upregulated (after stroke) experience-induced plastic changes are compromised.

In a healthy brain, the enzymatic activity of MMPs has plasticity promoting effects (Milward et al., 2007; Huntley, 2012). Consequently to increased neuronal activity, activated MMPs can lessen physical barriers (loosen up the ECM) or via the degradation of certain receptors influence signaling pathways. Such changes within neuronal cells and their synapses thereby alter the structure and activity of neuronal networks (Milward et al., 2007; Huntley, 2012). Involvement of MMPs in synaptic circuit remodeling has been mainly studied in the hippocampus, yet, their abundant expression in the central nervous system (CNS) indicates a much broader function. For instance, MMP9-deficient mice showed modestly reduced experience-dependent plasticity in the barrel cortex (Kaliszewska et al., 2012) and MMP3-deficient mice displayed abnormal neuronal morphology in the visual cortex and impaired plasticity induced by long-term monocular enucleation (Aerts et al., 2014). Here, we used a different approach to probe the role of MMPs in experience-induced changes in the visual system: we performed the experiments in wild type mice and treated them with the broad-spectrum inhibitor GM6001 or vehicle during 7 days of MD. Consistent with previous findings (Gordon and Stryker, 1996; Sawtell et al., 2003; Sato and Stryker, 2008), the OD-shift of vehicle-treated mice was mediated by open-eye potentiation. In contrast, there was no change in the open nor in the closed eye responses and hence no OD-plasticity in V1 after MD in GM6001-treated adult mice. This is in line with recent observations from juvenile rats, in which chronic treatment with GM6001 also prevented open eye potentiation after 7 days of MD (Spolidoro et al., 2012). However, treatment in this study only partially prevented the OD-shift, as there was no effect on the reduction of deprived eye responses (Spolidoro et al., 2012). A reduction in deprived eye responses in V1 is mostly observed in juvenile rodents after 3-4 days of MD (Gordon and Stryker, 1996), unless different raising conditions are used such as enriched environment or running wheel (Greifzu et al., 2014; Kalogeraki et al., 2014). In adult, standard-cage raised mice, 6-7 days of MD are necessary for significant OD-shifts and changes are mainly mediated by increases of open eye responses in V1 (Gordon and Stryker, 1996; Sawtell et al., 2003; Sato and Stryker, 2008). MMP9 activity was suggested in the potentiation of the open eye responses in juvenile rats, as treatment with GM6001 significantly reduced MMP9-mRNA expression only in the hemisphere where structural changes took place (Spolidoro et al., 2012). Since we observed a full blockade of plasticity after GM6001-treatment, it would be of interest to determine whether MMP9 is crucial for open-eye potentiation also in the adult brain. MMP9 has been widely investigated in various plasticity paradigms (Milward et al., 2007; Frischknecht and Gundelfinger, 2012; Huntley, 2012; Tsilibary et al., 2014) and one of the molecules shown to stimulate MMP9 secretion and expression in vitro and in vivo is Tumor Necrosis Factor alpha (TNFalpha) (Hanemaaijer et al., 1993; Candelario-Jalil et al., 2007). TNFalpha signaling was found to play an important role in the open eye potentiation in juvenile (Kaneko, et al., 2008), but not in adult V1 plasticity (Ranson et al., 2012), and since our data reveal that MMPs are indispensable for adult V1 plasticity, MMP-activation in the adult brain is most likely not dependent on TNFalpha signaling. Accordingly, this adds to the notion that juvenile and adult V1 plasticity depend on different molecular mechanisms (Hofer et al., 2006; Sato and Stryker, 2008; Ranson et al., 2012). Together, our new data demonstrate a vital role of MMPs for adult visual cortex plasticity, in particular for the increase of open eye responses in V1 after MD, and notably expand the previous studies from juvenile rats.

Under normal conditions, MMP-activity supports healthy brain development and function; yet a different outcome of MMP action has been described for diseased brain (Agrawal et al., 2008). Under pathophysiological conditions like inflammation, infection or stroke, uncontrolled MMP driven proteolysis can lead to negative consequences (Rosenberg et al., 1996; Rosenberg, 2002; Agrawal et al., 2008). Excessive MMP-activity after stroke caused blood brain barrier disruption, upregulation of inflammatory mediators, excitotoxicity and eventually cell death (Romanic et al., 1998; Lo et al., 2002; Gu et al., 2005; Wang and Tsirka, 2005; Yong, 2005; Morancho et al., 2010; Chang et al., 2014; Vandenbroucke and Libert, 2014). Recent studies reported increased enzymatic MMP9 activity within 24 h after a PT-stroke, and application of a broad spectrum MMP-inhibitor (FN-439) applied at the time of stroke induction, partially rescued impaired barrel cortex plasticity (Cybulska-Klosowicz et al., 2011; Liguz-Lecznar et al., 2012). Here we tested whether inhibition of upregulated MMP-activity (resulting from PT-stroke) may rescue cortical plasticity also when the treatment starts after lesion induction. Indeed, a single GM6001-treatment after PT in the neighboring S1 fully rescued plasticity in both of our experimental paradigms, OD- and interocular plasticity. Importantly, successful treatment did not have to start immediately after stroke induction (1 h) because treatment 24 h after had the same beneficial effect, highlighting the therapeutic potential of brief MMP-inhibition for stroke recovery. Beneficial treatment was, however, dependent on the number of injections: a single but not two-times injection of the MMP-inhibitor rescued OD-plasticity. The reduced plasticity-promoting effect in V1 of mice treated twice with GM6001 is likely due to too excessive MMP-downregulation, which in turn interfered with MMP facilitation of MD-induced plasticity. Consistent with this interpretation, it was reported that a particular dosage, timing as well as duration of MMPs-inhibition mattered for reduciton of lesion sizes after intracerebral hemorrhage, blood brain barrier permability or neurovascular remodeling in post-stroke period (Wang and Tsirka, 2005; Zhao et al., 2006; Sood et al., 2008; Chang et al., 2014). Together with the results from healthy animals, our data suggest that the plasticity-promoting effects of MMPs are dependent on a well-balanced level of activation, and if that balance is disturbed, experience-induced plastic changes are compromised.

There are several plausible mechanisms by which MMP-inhibition rescues OD-plasticity after stroke in S1. Stroke influences brain function in numerous ways e.g., causing inflammation and apoptosis, or disrupting the tightly regulated balance of neuronal inhibition and excitation (Neumann-Haefelin et al., 1995; Schiene et al., 1996; Witte and Stoll, 1997; Que et al., 1999a; 1999b; Witte et al., 2000) also in perilesional areas (Murphy and Corbett, 2009). One of the major consequences of ischemic damage is an elevated level of the neurotransmitter glutamate, leading to excitotoxicity and neuronal death (Lai et al., 2014). On the other hand, stroke can lead to increased tonic inhibition in the peri-infarct zone, and reducing this inhibition can promote functional recovery (Clarkson et al., 2010). In addition, focal ischemia can induce spreading depression within ipsilateral cortex (Schroeter et al., 1995) and a recent study showed that this phenomenon upregulated MMPs, leading to a breakdown of the blood brain barrier, edema, and vascular leakage, which was suppressed by GM6001 treatment (Gursoy-Ozdemir et al., 2004). Thus, it is likely that treatment with GM6001 shortly after the stroke (as in the present study) downregulated MMPs, thus reduced spreading depression, improved disturbed excitation/inhibition balance and allowed plastic changes to occur.

Although, we observed clear functional rescue of OD-plasticity after GM6001-treatment, there was no apparent effect on the lesion size: the PT-lesions in GM6001-treated mice were not smaller compared to vehicle-injected mice. This is in line with a recent observation, that a different broad-spectrum MMP-inhibitor (FN-143) did not attenuate brain damage resulting from photothrombosis, but partially rescued barrel cortex plasticity (Cybulska-Klosowicz et al., 2011). The present results, together with the above mentioned study, are not easy to reconcile with findings where MMP-inhibitors reduced the volume of a brain injury (Gu et al., 2005; Wang and Tsirka, 2005; Vandenbroucke and Libert, 2014). The difference might arise from the method used for stroke induction, dosage of inhibitors, timing and duration of the treatment and severity of the lesion.

Behavioral vision tests additionally revealed an involvement of MMPs for interocular plasticity during MD. The optomotor reflex is known to be mediated by subcortical pathways (Giolli et al., 2006). While visual capabilities measured by optomotry mainly reflect the properties of the retinal ganglion cells that project to these subcortical structures (Douglas et al., 2005), daily testing in the optomotor setup after MD induces a cortex-dependent and experience-enabled enhancement of spatial vision through the open eye (Prusky et al., 2006). Although inflammation was shown to interfere with the experience-enabled optomotor changes (Greifzu et al., 2011), little is known about the cellular origins or signaling pathways responsible for this plasticity paradigm. Here, we found that daily application of the MMP-inhibitor during MD prevented enhancements in both the spatial frequency and contrast sensitivity thresholds of the optomotor reflex of the open eye, while vehicle-treated control mice displayed the typical experience-enabled optomotor improvements. On the other hand, treatment of mice with the same inhibitor once or twice following cortical stroke rescued the impaired optomotor improvements. Thus, in contrast to the OD-plasticity results, rescue of optomotor improvements was present regardless of the duration of the treatment, adding to the idea that separate mechanisms and different neuronal circuits are responsible for OD- and interocular plasticity (Greifzu et al., 2011; 2014; Kang et al., 2013). Together, our results establish a novel function of MMPs in experience-enabled enhancements of the optomotor reflex of the open eye after MD in adult mice.

In conclusion, our present data highlight a critical role of MMPs in adult visual plasticity. They further suggest that upregulation of MMP-activity shortly after a cortical lesion compromises experience-induced visual plasticity, which in turn can be rescued by brief MMP-inhibition. Precise regulation of MMP-activity therefore seems to be essential for facilitating plasticity in the adult brain and offers new opportunities in treatment and recovery after stroke. It remains to be determined which particular MMPs account for the present results.

All experimental procedures were approved by the local government (Niedersächsisches Landesamt für Verbraucherschutz und Lebensmittelsicherheit, registration number 33.9-42502-04-10/0326).

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Author details

1. Justyna Pielecka-Fortuna

   Department of Systems Neuroscience, Bernstein Focus Neurotechnology, Johann-Friedrich-Blumenbach Institute for Zoology and Anthropology, University of Göttingen, Göttingen, Germany

   Contribution

   JPF, Conception and design; Acquisition of data; Analysis and interpretation of data; Drafting or revising the article

   For correspondence

   jpielec@gwdg.de

   Competing interests

   The authors declare that no competing interests exist.

2. Evgenia Kalogeraki

   1. Department of Systems Neuroscience, Bernstein Focus Neurotechnology, Johann-Friedrich-Blumenbach Institute for Zoology and Anthropology, University of Göttingen, Göttingen, Germany
   2. Göttingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences, University of Göttingen, Göttingen, Germany

   Contribution

   EK, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

3. Michal G Fortuna

   1. Institute for Neurophysiology and Cellular Biophysics, University Medical Center, Göttingen, Germany
   2. German Primate Center, Göttingen, Germany

   Contribution

   MGF, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

4. Siegrid Löwel

   Department of Systems Neuroscience, Bernstein Focus Neurotechnology, Johann-Friedrich-Blumenbach Institute for Zoology and Anthropology, University of Göttingen, Göttingen, Germany

   Contribution

   SL, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

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