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. 2002 May 28;99(11):7717-21.
doi: 10.1073/pnas.102088899.

Permissive proteolytic activity for visual cortical plasticity

Nobuko Mataga  1 , Nobuo Nagai, Takao K Hensch
Affiliations

Permissive proteolytic activity for visual cortical plasticity

Nobuko Mataga et al. Proc Natl Acad Sci U S A. .

Abstract

The serine protease, tissue-type plasminogen activator (tPA) is a key regulator of extracellular proteolytic cascades. We demonstrate a requirement for tPA signaling in the experience-dependent plasticity of mouse visual cortex during the developmental critical period. Proteolytic activity by tPA in the binocular zone was typically increased within 2 days of monocular deprivation (MD). This regulation failed to occur in glutamic acid decarboxylase (GAD) 65 knockout mice, an animal model of impaired ocular dominance plasticity because of reduced gamma-aminobutyric acid (GABA)-mediated transmission described previously. Loss of responsiveness to the deprived eye consequent to MD was conversely suppressed in mice lacking tPA despite normal levels of neuronal activity. Plasticity was restored in a gene dose-dependent manner, or by direct tPA infusion. Permissive amounts of tPA may, thus, couple functional to structural changes downstream of the excitatory-inhibitory balance that triggers visual cortical plasticity. Our results not only support a molecular cascade leading to neurite outgrowth after sensory deprivation, but also identify a valuable tool for further proteomic and genomic dissection of experience-dependent plasticity downstream of electrical activity.

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Figures

Figure 1
Figure 1
(A) Central visual pathways in mice. Contralateral eye input projects to all of primary visual cortex (V1) via the lateral geniculate nucleus (LGN). Ipsilateral eye afferents innervate only the lateral one third of V1 [binocular zone (BZ)], where most cells respond to both eyes viewing the central 30° of visual space. (B) Basal tPA activity levels in binocular zone of WT, tPA Het, tPA KO, and GAD65 KO (18, 19). Note normal basal tPA levels in GAD65 KO mice. ***, P < 0.005 vs. WT. (C) tPA proteolytic activity in WT mouse V1 after monocular deprivation (MD) during critical period. Significant elevation in both hemispheres after left eye occlusion for 1, 2, 4, or 7 days (at P25–26). Six mice per group. *, P < 0.05, **, P < 0.01, Student's t test vs. no MD (13 ± 0.4 ng/mg protein). (D) GAD65 KO mice fail to regulate tPA activity after brief MD (2 days), reflecting impaired plasticity in visual cortex (18). *, P < 0.05 vs. no MD WT. Number of mice per group is indicated above each bar in B and D.
Figure 2
Figure 2
(A) Ocular dominance histograms for WT mice (non-MD, four mice) normally shift toward ipsilateral, open eye (open circle) after short-term MD of contralateral input (filled circle, 4 days, STMD; 10 mice. P < 0.0001, χ2-test vs. non-MD) or long-term MD spanning the critical period (2 wk, LTMD; 10 mice, P < 0.0001, χ2-test vs. non-MD). (B) Distribution of non-MD tPA KO mice is similar to WT (seven mice, P = 0.51, χ2-test vs. non-MD WT). However, MD effects are weaker in tPA KO mice after both STMD (11 mice, P < 0.001, χ2-test vs. STMD in WT) and LTMD (10 mice, P < 0.0001, χ2-test vs. LTMD in WT). Contralateral bias index (CBI) in upper right corner ranges from 0 to 1 and decreases when plasticity occurs (18, 22). Number of cells per ocular dominance group is indicated above each bar.
Figure 3
Figure 3
(A) Summary of MD effect in WT and tPA KO mice. Each symbol represents CBI value of individual animals (open circles, WT; filled circles, KO). Plasticity is consistently and significantly suppressed in all tPA KO mice after both STMD (CBI ± SD = 0.66 ± 0.06 vs. 0.49 ± 0.05, KO and WT) and LTMD (0.69 ± 0.06 vs. 0.44 ± 0.04). Shaded region indicates range of nondeprived CBI for both WT (0.73 ± 0.02) and KO mice (0.76 ± 0.04). ***, P < 0.001, Student's t test. (B) Diazepam (DZ, 2 mg/ml) fails to restore plasticity to tPA KO mice. Neither drug nor vehicle (Veh, 50% propylene glycol) infusion daily throughout brief MD (P26–30) enables the expected decrease in CBI. (C) No gross disruption of neuronal activity in tPA KO mice is observed by egr-1 mRNA expression with respect to WT under three conditions: normal light/dark cycle (L), 5 days complete darkness (D), and 30 min photo-stimulation (1 Hz, 20 J) after dark-adaptation (P). Expression was normalized by housekeeping gene G3PDH. *, P < 0.05, **, P < 0.01, ***, P < 0.001, Student's t test vs. D value.
Figure 4
Figure 4
(A) Permissive levels of tPA restore ocular dominance plasticity. Short-term MD during the critical period slightly reduces CBI values in tPA Het from non-MD levels (0.64 ± 0.02 and 0.77 ± 0.02, respectively) but does not reach WT levels (shaded zone; P < 0.001, Student's t test vs. STMD for WT in Fig. 3A) and is no better than tPA KO levels (P = 0.5 vs. STMD for KO in Fig. 3A). With long-term MD, CBI values in tPA Het (0.53 ± 0.07) are significantly reduced from brief MD and tPA KO (P < 0.001 vs. LTMD for KO in Fig. 3A). Late MD effects in tPA Het (late-LTMD at P60; 0.66 ± 0.05) are negligible in postcritical period adult animals similar to WT (CBI = 0.65 ± 0.07, n = 4; P = 0.8). (B) Monocular TTX injections (4 days) during the critical period significantly reduce CBIs in tPA Het compared with brief MD (P < 0.01 vs. STMD for Het in A), but remain weaker than in WT mice (CBI = 0.54 ± 0.05 and 0.39 ± 0.10, Het vs. WT). Note monocular TTX produces more powerful plasticity than eyelid suture (shaded zone) in WT animals (18). (C) Direct intracranial infusion of recombinant tPA during 1-wk MD (7 days from P25–26) restores plasticity to tPA KO mice. No gross abnormalities were observed after tPA injections (not shown). (CBI = 0.44 ± 0.02, 0.69 ± 0.01, and 0.54 ± 0.01 for WT, vehicle KO, and tPA KO, respectively). *, P < 0.05; **, P < 0.01; ***, P < 0.005, Student's t test.
Figure 5
Figure 5
Proposed molecular cascade of visual cortical plasticity. Inhibitory-excitatory balance detects perturbed sensory input (18)(a). Neuromodulators (b) regulate coupling (29) to protein kinase A (30)(c); phosphorylation of MAP kinase (35) and CREB (24) (d) reciprocally induces and is stimulated by BDNF (34)(e), which is known to release tPA from cortical neurons (33).
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