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. 2022 Feb 23;23(5):2438.
doi: 10.3390/ijms23052438.

Chronic Monocular Deprivation Reveals MMP9-Dependent and -Independent Aspects of Murine Visual System Plasticity

Sachiko Murase  1 , Sarah E Robertson  2 , Crystal L Lantz  1 , Ji Liu  1 , Daniel E Winkowski  1 , Elizabeth M Quinlan  1
Affiliations

Chronic Monocular Deprivation Reveals MMP9-Dependent and -Independent Aspects of Murine Visual System Plasticity

Sachiko Murase et al. Int J Mol Sci. .

Abstract

The deletion of matrix metalloproteinase MMP9 is combined here with chronic monocular deprivation (cMD) to identify the contributions of this proteinase to plasticity in the visual system. Calcium imaging of supragranular neurons of the binocular region of primary visual cortex (V1b) of wild-type mice revealed that cMD initiated at eye opening significantly decreased the strength of deprived-eye visual responses to all stimulus contrasts and spatial frequencies. cMD did not change the selectivity of V1b neurons for the spatial frequency, but orientation selectivity was higher in low spatial frequency-tuned neurons, and orientation and direction selectivity were lower in high spatial frequency-tuned neurons. Constitutive deletion of MMP9 did not impact the stimulus selectivity of V1b neurons, including ocular preference and tuning for spatial frequency, orientation, and direction. However, MMP9-/- mice were completely insensitive to plasticity engaged by cMD, such that the strength of the visual responses evoked by deprived-eye stimulation was maintained across all stimulus contrasts, orientations, directions, and spatial frequencies. Other forms of experience-dependent plasticity, including stimulus selective response potentiation, were normal in MMP9-/- mice. Thus, MMP9 activity is dispensable for many forms of activity-dependent plasticity in the mouse visual system, but is obligatory for the plasticity engaged by cMD.

Keywords: MMP9; calcium imaging; chronic monocular deprivation; ocular dominance.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
cMD decreases the strength of the deprived eye pathway in WT but not MMP9−/− mice. (A) Left: Experimental timeline. MD was initiated at eye opening (postnatal day 14 (P14)) and maintained until adulthood (>P90). Right: GCaMP6s expression was targeted to layer 2/3 neurons of WT V1b (AAV1.hSyn1.mRuby2.GSG.P2A.GCaMP6s.WPRE.SV40, Addgene, titer: 1.3 × 1013 U/mL, 30 nl, AP: 1.0 mm, MD: −3.0 mm, DV: 0.3 mm; at least 3 weeks prior to imaging) to monitor visual evoked calcium transients. (B) Representative ΔF/F of the GCaMP6s signal evoked in layer 2/3 of V1b in normal reared (NR) and cMD WTs in response to the presentation of drifting square wave gratings (0.05 cycle/degree, 100% contrast, 28 cd/m2 at 12 orientations) to contra- and ipsilateral eyes. Blue bar = stimulus onset. Individual trials in grey, average of 5 repeats in black. Ocular dominance score (ODS) = (C − I)/(C + I) was calculated at the preferred orientation for each neuron. (C) Examples of two-photon field views of GCaMP6s expression. (D) Cumulative distribution of ODS. * p = 1.0 × 10−4, KS test. (E) Mean CBI of layer 2/3 neurons is significantly lower in cMD than NR WT mice. * p = 0.012, Mann−Whitney test. n = 5 subjects. (F) Cumulative distribution of contra and ipsi eye neuronal responses (ΔF/F; * p = 8.3 × 10−29 for contra, p = 0.91 for ipsi, Student’s t-test, 365 and 201 neurons for NR and cMD, respectively).
Figure 2
Figure 2
Ocular dominance in MMP9−/− mice is normal and resistant to cMD. (A) Left: Experimental timeline. Right: GCaMP6s expression was targeted to layer 2/3 neurons of MMP9−/− V1b. (B) Representative ΔF/F of GCaMP6 signal evoked in layer 2/3 of V1b in normal reared (NR) and cMD MMP9−/− mice in response to presentation of drifting square wave gratings (0.05 cycle/degree, 1 Hz, 100% contrast, 28 cd/m2 at 12 orientations) to contra- and ipsilateral eyes. Red bar = stimulus onset. Individual trials in grey, average of 5 repeats in black. Ocular dominance score (OD score) = (C − I)/(C + I) was calculated at the preferred orientation for each neuron. (C) Examples of two-photon field views of GCaMP6s expression. (D) Cumulative distribution of ODS (p = 0.42, KS test). (E) Mean CBI of layer 2/3 neurons is similar in cMD and NR MMP9−/− mice. p = 0.38, Mann−Whitney test. n = 6 subjects. (F) Cumulative distribution of contra and ipsi eye visual responses (ΔF/F; p = 0.75 for contra, p = 0.63 for ipsi, Student’s t-test, 328 and 595 neurons for NR and cMD, respectively).
Figure 3
Figure 3
Stability of GCaMP6s expression and visually responsive neurons over experimental conditions. (A) Left: representative neuron from layer 2/3 of V1b expressing GCaMP6s. Right: Quantification of fluorescence along dashed white line reveals a high signal in the cytoplasm relative to the nucleus. (B) Top: No difference in the total number of GCaMP6s expressing neurons between WT and MMP9−/−, normal reared (NR) and cMD subjects (one-way ANOVA, F = 3.0, p = 0.06, n = 5 and 6 subjects for WT and MMP9−/− mice, respectively). Bottom: Percent of GCaMP6s expressing neurons that are visually-responsive (one-way ANOVA, F = 0.96, p = 0.43). A neuron is defined as visually responsive if the mean ΔF value in response to a visual stimulus of any direction exceeds 3 × STD of baseline (F0) for > 40% of trials during either contra or ipsi eye stimulation. (C) Coefficient of variance (CV) of calcium transients (standard deviation over mean ΔF/F (STD/mean) is comparable across all experimental conditions, and is unaffected by the deletion of MMP9 or cMD. Box plots represent the median as a bar, 25th to 75th percentile as box, and max and min as whiskers (WT: one-way ANOVA, F = 7.1, p = 0.10, n = 359, 364, 201, and 194 neurons for NR contra, NR ipsi, cMD deprived, and cMD non-deprived, respectively; MMP9−/−: one-way ANOVA, F = 4.3, p = 0.11, n = 315, 321, 595, and 595 neurons for NR contra, NR ipsi, cMD deprived, and cMD non-deprived, respectively).
Figure 4
Figure 4
Distributions of ocular dominance scores are independent of the criterion for neuronal visual responsivity. Number of neurons in different ODS categories (ODS = 1, 1 > ODS ≥ 0.6, 0.6 > ODS ≥ 0.2, 0.2 > ODS ≥ −0.2, −0.2 > ODS ≥ −0.6, −0.6 > ODS ≥ −1, and ODS = −1) following different inclusion criteria for visually-responsive neuronal activity (thickest to thinnest lines: 3×, 4×, 5×, 6×, 7×, and 8× STD of baseline).
Figure 5
Figure 5
cMD impairs the strength of visual responses across contrasts and spatial frequencies in WT, but not MMP9−/− mice. (A) Experimental paradigm. (B) Significant decrease in the strength of neuronal responses to a range of contrasts (top) and spatial frequencies (bottom) in cMD versus NR WT (left), but not in MMP9−/− (right) mice. Mean ΔF/F values of responsive neurons are plotted for NR (dark blue) and cMD (light blue) for WT, NR (red) and cMD (orange) for MMP9−/− (repeated measures ANOVAs: contrast at 0.05 cpd, WT F = 9.7, * p = 0.014, MMP9−/− F = 0.20, p = 0.67; spatial frequency at 100% contrast: WT F = 8.3, * p = 0.020, MMP9−/− F = 0.33, p = 0.58; n = 5 subjects). (C) Distribution of the spatial frequency evoking the peak neuronal response. Right: NR WT (dark blue) and cMD WT (light blue). Left: NR MMP9−/− (red) and cMD MMP9−/− (orange). Mean ± SEM, n = 5 subjects. (D) Mean peak spatial frequency is similar in cMD and NR in both WT and MMP9−/− mice (one-way ANOVA, F = 0.89, p = 0.47, n = 5 subjects).
Figure 6
Figure 6
Orientation and direction selectivity are impacted by cMD in WT but not MMP9−/− mice. (A) Representative polar plots of low spatial frequency (SF) tuned (0.05 cpd) and high SF tuned (>0.05 cpd) neurons of WT and MMP9−/− mice. NR WT (dark blue) and cMD WT (light blue), NR MMP9−/− (red), and cMD MMP9−/− (orange). Scale: ΔF/F (%). (B) cMD significantly decreased ΔF/F in WT but not MMP9−/− mice. (C) Orientation selectivity (1-CV) in high SF tuned (>0.05 cpd) neurons is lower in cMD (light blue) than NR (dark blue) WT (left) but not MMP9−/− (right, red for NR and orange for cMD) mice. (D) Direction selectivity (1-dirCV) is higher in low SF tuned neurons (0.05 cpd) in cMD (light blue) than NR (dark blue), and lower in high SF tuned (>0.05 cpd) neurons in cMD WT, but not in MMP9−/− mice. Box plots represent median as a bar, 25th to 75th percentile as box, and max and min as whiskers, * p < 0.05, ** p < 0.001, Student’s t-test, n = 59, 51, 94, 95, 208, 88, 104, and 160 neurons for LSF NR WT, LSF cMD WT, HSF NR WT, HSF cMD WT, LSF NR MMP9−/−, LSF cMD MMP9−/−, HSF NR MMP9−/−, and HSF cMD MMP9−/−, respectively.
Figure 7
Figure 7
Stimulus-Selective Response Potentiation persists in adult MMP9−/− mouse V1b. Top: Experimental timeline. Middle: Representative layer 4 VEPs of WT and MMP9−/− mice in response to the initial 200 presentations of visual stimulation at a single orientation (0.05 cpd 100% contrast gratings reversing at 1 Hz), and a familiar and novel stimuli presented 24 h later. Bottom: Mean VEP amplitudes in WT and MMP9−/− mice. Grey bar = mean ± SEM of initial VEP; 24 h later, a significant increase in the VEP amplitude is observed in response to the familiar (left) but not novel (right) stimulus orientation, in both WT and MMP9−/− mice, * p < 0.05, Student’s t-test. n = 6 and 5 subjects for WT and MMP9−/−, respectively.
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