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.
Highlights
Many studies have investigated the segregation of ON and OFF pathways in the retina during postnatal development, and much is known about the structural maturation of different subtypes of retinal ganglion cells (RGCs) [1,2]
Based upon the sublamina in which RGC dendrites arborize in the inner plexiform layer (IPL), RGCs can be classified into three subtypes: ON, OFF, and ON-OFF, which presumably respond to light onset, light offset, and both [3,4,5]
With the Spike Triggered Covariance (STC)-NC, we found that ON-OFF cells in NT-3 OE mice exhibited significantly smaller receptive field (RF) centers compared to WT retinas at P18 (WT: 15.660.46103 mm2; n = 118; NT-3 OE: 13.760.36103 mm2, n = 170; p,0.001 in Wilcoxon rank sum, Fig. 8B–C)
Summary
Many studies have investigated the segregation of ON and OFF pathways in the retina during postnatal development, and much is known about the structural maturation of different subtypes of retinal ganglion cells (RGCs) [1,2]. Based upon the sublamina in which RGC dendrites arborize in the inner plexiform layer (IPL), RGCs can be classified into three subtypes: ON, OFF, and ON-OFF, which presumably respond to light onset, light offset, and both [3,4,5]. RGCs acquire their final dendritic branching pattern and territories in a subtype-dependent manner [6,7,8,9]. The fraction of bistratified RGCs decreases as they are converted into monostratified cells during the first postnatal month [8,10]. While RGCs having dendrites monostratified in the ON sublamina continue to expand their dendritic field size by adding new branches following eye-opening, bistratified RGCs acquire their final morphology by the time of eye opening [8,9]
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