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Non-centered spike-triggered covariance analysis reveals neurotrophin-3 as a developmental regulator of receptive field properties of ON-OFF retinal ganglion cells.

Cantrell DR, Cang J, Troy JB, Liu X - PLoS Comput. Biol. (2010)

Bottom Line: Using this new tool, we find that RGCs gradually develop sensitivity to focal stimulation after eye opening, that the percentage of ON-OFF center cells decreases with age, and that RF centers of ON and ON-OFF cells become smaller.Overexpression of NT-3 leads to the precocious maturation of RGC responsiveness and accelerates the developmental decrease of RF center size in ON-OFF cells.In summary, our study introduces STC-NC analysis which successfully identifies subtype RGCs and demonstrates how RF development relates to a neurotrophic driver in the retina.

View Article: PubMed Central - PubMed

Affiliation: Interdepartmental Neuroscience Program, Northwestern University, Evanston, Illinois, USA.

ABSTRACT
The functional separation of ON and OFF pathways, one of the fundamental features of the visual system, starts in the retina. During postnatal development, some retinal ganglion cells (RGCs) whose dendrites arborize in both ON and OFF sublaminae of the inner plexiform layer transform into RGCs with dendrites that monostratify in either the ON or OFF sublamina, acquiring final dendritic morphology in a subtype-dependent manner. Little is known about how the receptive field (RF) properties of ON, OFF, and ON-OFF RGCs mature during this time because of the lack of a reliable and efficient method to classify RGCs into these subtypes. To address this deficiency, we developed an innovative variant of Spike Triggered Covariance (STC) analysis, which we term Spike Triggered Covariance - Non-Centered (STC-NC) analysis. Using a multi-electrode array (MEA), we recorded the responses of a large population of mouse RGCs to a Gaussian white noise stimulus. As expected, the Spike-Triggered Average (STA) fails to identify responses driven by symmetric static nonlinearities such as those that underlie ON-OFF center RGC behavior. The STC-NC technique, in contrast, provides an efficient means to identify ON-OFF responses and quantify their RF center sizes accurately. Using this new tool, we find that RGCs gradually develop sensitivity to focal stimulation after eye opening, that the percentage of ON-OFF center cells decreases with age, and that RF centers of ON and ON-OFF cells become smaller. Importantly, we demonstrate for the first time that neurotrophin-3 (NT-3) regulates the development of physiological properties of ON-OFF center RGCs. Overexpression of NT-3 leads to the precocious maturation of RGC responsiveness and accelerates the developmental decrease of RF center size in ON-OFF cells. In summary, our study introduces STC-NC analysis which successfully identifies subtype RGCs and demonstrates how RF development relates to a neurotrophic driver in the retina.

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STC-NC analysis reveals smaller RF center size of ON-OFF cells in NT-3 OE mice.(A) ON and ON-OFF RGCs in NT-3 OE retinas had smaller RF centers at P18 than WT mice. (D) At P25, only ON-OFF RGCs in NT-3 OE had smaller RF centers compared to WT. (B–C, E–F) Cumulative distributions of RF sizes for ON (B, E) and ON-OFF cells (C, F) in WT and NT-3 OE retinas at P18 (B–C) and P25 (E–F).
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pcbi-1000967-g008: STC-NC analysis reveals smaller RF center size of ON-OFF cells in NT-3 OE mice.(A) ON and ON-OFF RGCs in NT-3 OE retinas had smaller RF centers at P18 than WT mice. (D) At P25, only ON-OFF RGCs in NT-3 OE had smaller RF centers compared to WT. (B–C, E–F) Cumulative distributions of RF sizes for ON (B, E) and ON-OFF cells (C, F) in WT and NT-3 OE retinas at P18 (B–C) and P25 (E–F).

Mentions: (A) Both ON and ON-OFF RGCs show a decrease in RF center size at P25 compared to P18, while the size of OFF RGC RF centers is unchanged. (B) Cumulative distributions of RF center sizes for ON, OFF, and ON-OFF cells in WT. *: p<0.05; ***: p<0.001 in Wilcoxon rank sum test (same in Fig. 8). (C) The correlation between the STC-NC signal strength and RF size is negative for WT P18 (black) and P25 (gray) ON cells. The ANCOVA technique removes the effect of the confounding STC-NC signal strength prior to calculating the significance of differences in RF size due to grouping. The parallel lines represent best fits. Following standard ANCOVA analysis, the parallel condition was enforced after demonstrating that the slopes of the lines of best fit through the two data sets were not significantly different and that P25 had smaller RF sizes than P18 for WT ON cells ( p = 4×10−5 in ANCOVA test).


Non-centered spike-triggered covariance analysis reveals neurotrophin-3 as a developmental regulator of receptive field properties of ON-OFF retinal ganglion cells.

Cantrell DR, Cang J, Troy JB, Liu X - PLoS Comput. Biol. (2010)

STC-NC analysis reveals smaller RF center size of ON-OFF cells in NT-3 OE mice.(A) ON and ON-OFF RGCs in NT-3 OE retinas had smaller RF centers at P18 than WT mice. (D) At P25, only ON-OFF RGCs in NT-3 OE had smaller RF centers compared to WT. (B–C, E–F) Cumulative distributions of RF sizes for ON (B, E) and ON-OFF cells (C, F) in WT and NT-3 OE retinas at P18 (B–C) and P25 (E–F).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2958799&req=5

pcbi-1000967-g008: STC-NC analysis reveals smaller RF center size of ON-OFF cells in NT-3 OE mice.(A) ON and ON-OFF RGCs in NT-3 OE retinas had smaller RF centers at P18 than WT mice. (D) At P25, only ON-OFF RGCs in NT-3 OE had smaller RF centers compared to WT. (B–C, E–F) Cumulative distributions of RF sizes for ON (B, E) and ON-OFF cells (C, F) in WT and NT-3 OE retinas at P18 (B–C) and P25 (E–F).
Mentions: (A) Both ON and ON-OFF RGCs show a decrease in RF center size at P25 compared to P18, while the size of OFF RGC RF centers is unchanged. (B) Cumulative distributions of RF center sizes for ON, OFF, and ON-OFF cells in WT. *: p<0.05; ***: p<0.001 in Wilcoxon rank sum test (same in Fig. 8). (C) The correlation between the STC-NC signal strength and RF size is negative for WT P18 (black) and P25 (gray) ON cells. The ANCOVA technique removes the effect of the confounding STC-NC signal strength prior to calculating the significance of differences in RF size due to grouping. The parallel lines represent best fits. Following standard ANCOVA analysis, the parallel condition was enforced after demonstrating that the slopes of the lines of best fit through the two data sets were not significantly different and that P25 had smaller RF sizes than P18 for WT ON cells ( p = 4×10−5 in ANCOVA test).

Bottom Line: Using this new tool, we find that RGCs gradually develop sensitivity to focal stimulation after eye opening, that the percentage of ON-OFF center cells decreases with age, and that RF centers of ON and ON-OFF cells become smaller.Overexpression of NT-3 leads to the precocious maturation of RGC responsiveness and accelerates the developmental decrease of RF center size in ON-OFF cells.In summary, our study introduces STC-NC analysis which successfully identifies subtype RGCs and demonstrates how RF development relates to a neurotrophic driver in the retina.

View Article: PubMed Central - PubMed

Affiliation: Interdepartmental Neuroscience Program, Northwestern University, Evanston, Illinois, USA.

ABSTRACT
The functional separation of ON and OFF pathways, one of the fundamental features of the visual system, starts in the retina. During postnatal development, some retinal ganglion cells (RGCs) whose dendrites arborize in both ON and OFF sublaminae of the inner plexiform layer transform into RGCs with dendrites that monostratify in either the ON or OFF sublamina, acquiring final dendritic morphology in a subtype-dependent manner. Little is known about how the receptive field (RF) properties of ON, OFF, and ON-OFF RGCs mature during this time because of the lack of a reliable and efficient method to classify RGCs into these subtypes. To address this deficiency, we developed an innovative variant of Spike Triggered Covariance (STC) analysis, which we term Spike Triggered Covariance - Non-Centered (STC-NC) analysis. Using a multi-electrode array (MEA), we recorded the responses of a large population of mouse RGCs to a Gaussian white noise stimulus. As expected, the Spike-Triggered Average (STA) fails to identify responses driven by symmetric static nonlinearities such as those that underlie ON-OFF center RGC behavior. The STC-NC technique, in contrast, provides an efficient means to identify ON-OFF responses and quantify their RF center sizes accurately. Using this new tool, we find that RGCs gradually develop sensitivity to focal stimulation after eye opening, that the percentage of ON-OFF center cells decreases with age, and that RF centers of ON and ON-OFF cells become smaller. Importantly, we demonstrate for the first time that neurotrophin-3 (NT-3) regulates the development of physiological properties of ON-OFF center RGCs. Overexpression of NT-3 leads to the precocious maturation of RGC responsiveness and accelerates the developmental decrease of RF center size in ON-OFF cells. In summary, our study introduces STC-NC analysis which successfully identifies subtype RGCs and demonstrates how RF development relates to a neurotrophic driver in the retina.

Show MeSH
Related in: MedlinePlus