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. 2016 Sep 7;36(36):9472-8.
doi: 10.1523/JNEUROSCI.0580-16.2016.

Lynx1 Limits Dendritic Spine Turnover in the Adult Visual Cortex

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Free PMC article

Lynx1 Limits Dendritic Spine Turnover in the Adult Visual Cortex

Mari Sajo et al. J Neurosci. .
Free PMC article

Abstract

Dendritic spine turnover becomes limited in the adult cerebral cortex. Identification of specific aspects of spine dynamics that can be unmasked in adulthood and its regulatory molecular mechanisms could provide novel therapeutic targets for inducing plasticity at both the functional and structural levels for robust recovery from brain disorders and injuries in adults. Lynx1, an endogenous inhibitor of nicotinic acetylcholine receptors, was previously shown to increase its expression in adulthood and thus to limit functional ocular dominance plasticity in adult primary visual cortex (V1). However, the role of this "brake" on spine dynamics is not known. We examined the contribution of Lynx1 on dendritic spine turnover before and after monocular deprivation (MD) in adult V1 with chronic in vivo imaging using two-photon microscopy and determined the spine turnover rate of apical dendrites of layer 5 (L5) and L2/3 pyramidal neurons in adult V1 of Lynx1 knock-out (KO) mice. We found that the deletion of Lynx1 doubled the baseline spine turnover rate, suggesting that the spine dynamics in the adult cortex is actively limited by the presence of Lynx1. After MD, adult Lynx1-KO mice selectively exhibit higher rate of spine loss with no difference in gain rate in L5 neurons compared with control wild-type counterparts, revealing a key signature of spine dynamics associated with robust functional plasticity in adult V1. Overall, Lynx1 could be a promising therapeutic target to induce not only functional, but also structural plasticity at the level of spine dynamics in the adult brain.

Significance statement: Dendritic spine turnover becomes limited in the adult cortex. In mouse visual cortex, a premier model of experience-dependent plasticity, we found that the deletion of Lynx1, a nicotinic "brake" for functional plasticity, doubled the baseline spine turnover in adulthood, suggesting that the spine dynamics in the adult cortex is actively limited by Lynx1. After visual deprivation, spine loss, but not gain rate, remains higher in adult Lynx1 knock-out mice than in control wild-type mice, revealing a key signature of spine dynamics associated with robust functional plasticity. Lynx1 would be a promising target to induce not only functional, but also structural plasticity at the level of spine dynamics in adulthood.

Keywords: Lynx1; dendritic spine; plasticity; visual cortex.

Figures

Figure 1.
Figure 1.
Normal dendritic complexity and spine density of L5 and L2/3 V1 neurons in adult Lynx1-KO mice. A, 3D reconstruction of in vivo two-photon images of L5 pyramidal neuron in binocular zone of V1 of adult WT and Lynx1-KO mouse. Scale bar, 100 μm. B, Number of branching points of apical dendrite of L5 neurons (WT: n = 7 cells from 5 mice, KO: n = 9 cells from 6 mice). C, Spine density (number of spines per micrometer) of L5 neurons (WT: n = 11 cells from 5 mice, KO: n = 13 cells from 8 mice). D, 3D reconstruction of two-photon images of L2/3 pyramidal neurons. E, Number of branching points of apical dendrite of L2/3 neurons (WT: n = 6 cells from 4 mice, KO: n = 4 cells from 3 mice). F, Spine density (number of spines per micrometer) of L2/3 neurons (WT: n = 10 cells from 5 mice, KO: n = 10 cells from 7 mice). One to three dendrites were imaged from each cell to count the total spines in each cell. Data are presented as mean ± SEM.
Figure 2.
Figure 2.
Spine turnover of adult L5 and L2/3 V1 neurons is higher in Lynx1-KO mice than in WT mice. A, Repeated imaging of dendritic segments of adult L5 V1 pyramidal neurons over 4 d in adult WT mice and Lynx1-KO mice. Light green (WT) and green (KO) arrowheads indicate gained spine. Light magenta (WT) and magenta (KO) arrowheads indicate lost spine. Scale bar, 5 μm. One to three dendrites were imaged from each cell to count total, gained, and lost spines in each cell. B, Spine gain and loss rate of adult L5 V1 pyramidal neurons over 4 d are significantly higher in adult Lynx1-KO mice than in WT mice (WT: n = 11 cells from 5 mice, KO: n = 13 cells from 8 mice). C, Repeated imaging of dendritic segment of adult L2/3 V1 pyramidal neuron. D, Spine gain and loss rate of adult L2/3 V1 pyramidal neurons over 4 d were significantly higher in adult Lynx1-KO mice than in WT mice (WT: n = 10 cells from 5 mice, KO: n = 10 cells from 7 mice). Data are presented as mean ± SEM. **p < 0.01.
Figure 3.
Figure 3.
Spine loss rate of adult L5 V1 neurons is higher in Lynx1-KO mice than in WT mice during MD. A, Repeated imaging of dendritic segment of adult L5 neurons before (day 8) and after (day 12) MD (4dMD). Light green (WT) and green (KO) arrowheads indicate spine gain. Light magenta (WT) and magenta (KO) arrowheads indicate spine loss. One to three dendrites were imaged from each cell to count total, gained, and lost spines in each cell. Scale bar, 5 μm. B, Spine gain and loss rate after 4 d of MD. Spine loss rate was significantly higher in adult Lynx1-KO mice than in WT mice (WT: n = 11 cells from 5 mice, KO: n = 12 cells from 7 mice). **p < 0.01, Student's t test. C, Spine turnover rates over 4 d were plotted as a function of time. Light green, light magenta, green, and magenta indicate WT gain, WT loss, Lynx1-KO gain, and Lynx1-KO loss, respectively. MD occurred right after day 8 imaging. Initial statistical analysis was done using MANOVA, in which interactions among three factors: genotype (knock out/wild type), type (gain/loss), and time (day 4/day 8/day 12) were assessed. Turnover rates significantly differed between genotypes (KO vs WT, df = 42, exact F value = 113.18, p < 0.0001). Interaction between genotype and type was not statistically significant (df = 42, exact F value = 1.216, p = 0.277). Therefore, effects for “loss” or “gain” value were independently assessed with the generalized linear model, in which “genotype” and “time” were adopted as fixed-effects variables and “cell” was adopted as a random-effect variable. For loss rate, both “time” and “genotype” were statistically significant. (df = 52, F = 4.901 and p = 0.011 for time and F = 125.843 and p < 0.001 for genotype, respectively). As the result of post hoc pairwise comparisons using Bonferroni modification, loss values for KO were significantly different between day 12 and day 8 (p = 0.047. 95%CI: 0.019–4.262), whereas no other comparisons were statistically significant (KO: days 4–8, days 4–12 and WT: days 4–8, days 4–12, days 8–12). For gain rate, both “time” and “genotype” were statistically significant (df = 52, F = 43.439 and p < 0.001 for time and F = 92.171 and p < 0.001 for genotype, respectively). As the result of post hoc pairwise comparisons using Bonferroni modification, gain values for WT significantly differed in between day 8 and day 12 (p < 0.001. 95%CI: −9.754 to −5.463), whereas there was no significant difference for KO (days 8–12). Data are presented as mean ± SEM.
Figure 4.
Figure 4.
Spine gain and loss rates of adult L2/3 V1 neurons are higher in Lynx1-KO mice than in WT mice during MD. A, Repeated imaging of dendritic segment of adult L2/3 V1 neurons before (day 8) and after (day 12) MD. Light green (WT) and green (KO) arrowheads indicate spine gain. Light magenta (WT) and magenta (KO) arrowheads indicate spine loss. One to three dendrites were imaged from each cell to count total, gained, and lost spines in each cell. Scale bar, 5 μm. B, Spine gain and loss rate after 4 d of MD (4dMD). Spine loss rate was significantly higher in adult Lynx1-KO mice than in WT mice (WT: n = 10 cells from 5 mice, KO: 9 cells from 6 mice). **p < 0.01, Student's t test. C, Spine turnover rates over 4 d were plotted as a function of time. Light green, light magenta, green, and magenta indicate WT gain, WT loss, Lynx1-KO gain, and Lynx1-KO loss, respectively. MD occurred after day 8 imaging. Initial statistical analysis was done using MANOVA, in which interactions among three factors: genotype (knock out/wild type), type (gain/loss), and time (day 4/day 8/day 12) were assessed. Turnover rates significantly differed between genotype (KO vs WT, df = 35, exact F value = 164.860, p < 0.0001). The interaction between genotype and type was not statistically significant (df = 34, exact F value = 0.464, p = 0.500). Therefore, effects for the loss or gain value were assessed independently with ageneralized linear model, in which genotype and time were adopted as fixed-effect variables and cell was adopted as a random-effect variable. Genotype was statistically significant. (df = 42, F = 126.217 and p < 0.0001 for loss, df = 42, F = 199.452 and p < 0.0001 for gain), but time was not significant (df = 42, F = 1.708 and p = 0.193 for loss, df = 42, F = 1.047 and p = 0.360 for gain). Post hoc pairwise comparisons using Bonferroni modification did not detect any significant difference in any comparisons for loss or gain values. Data are presented as mean ± SEM.

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