Somal positioning and dendritic growth of horizontal cells are regulated by interactions with homotypic neighbors.

Retinal neurons extend their dendritic fields to achieve a degree of dendritic overlap with homotypic neighbors that is cell-type specific. How these neurons regulate their dendritic growth is unclear. The dendritic field of a retinal horizontal cell varies inversely with horizontal cell density across different strains of mice, suggesting that proximity to neighboring cells regulates dendritic growth. To test this directly, we have employed the Cre-loxP conditional gene targeting strategy to achieve inactivation of Lim1 function in developing horizontal cells. Through this approach, Lim1 function was prevented within a subset of horizontal cells that in turn fail to migrate to the horizontal cell layer and differentiate normally. For those remaining horizontal cells with Lim1 intact (about half of the normal population in these mice), we show that they spread themselves out tangentially and differentiate a dendritic morphology that is essentially normal but for the fact that it has nearly doubled in area. Such larger horizontal cells, sampling from an area of retina containing twice their normal afferent number, differentiate a dendritic field with nearly double the number of higher order branches and terminal clusters. These results demonstrate directly that positioning and dendritic growth are regulated by interactions with homotypic neighbors, whereas afferents instruct the differentiation of dendritic patterning.

Developmental regulation of the morphology of mouse retinal horizontal cells by visual experience.

Visual deprivation during development alters the normal refinement of connections, neurotransmitter expression and physiological function in the retina. We investigated the effects of different forms of visual experience on the anatomy of retinal neurons in the mouse. Although it is generally assumed that outer retinal cells are not affected morphologically by visual experience, we found changes in the outer retinas of animals reared with light but no contrast. In postnatal day 30 animals reared in control, dark and high-contrast environments, horizontal-cell processes ramified normally in the outer plexiform layer. However, in postnatal day 30 no-contrast-reared retinas, horizontal-cell processes emerged from the outer plexiform layer and ramified in the inner nuclear layer. Similar sprouting processes of horizontal cells were found in a mouse model of retinitis pigmentosa. In conclusion, our data show that a lack of contrast during development alters the morphology of horizontal cells and may thus affect normal visual processing. This effect may be relevant for young patients with cloudy vision (e.g. cataract).

Light triggers expression of philanthotoxin-insensitive Ca2+-permeable AMPA receptors in the developing rat retina.

Ca2+-permeable AMPA receptors (AMPARs) are expressed throughout the adult CNS but yet their role in development is poorly understood. In the developing retina, most investigations have focused on Ca2+ influx through NMDARs in promoting synapse maturation and not on AMPARs. However, NMDARs are absent from many retinal cells suggesting that other Ca2+-permeable glutamate receptors may be important to consider. Here we show that inhibitory horizontal and AII amacrine cells lack NMDARs but express Ca2+-permeable AMPARs. Before eye-opening, AMPARs were fully blocked by philanthotoxin (PhTX), a selective antagonist of Ca2+-permeable AMPARs. After eye-opening, however, a subpopulation of Ca2+-permeable AMPARs were unexpectedly PhTX resistant. Furthermore, Joro spider toxin (JSTX) and IEM-1460 also failed to antagonize, demonstrating that this novel pharmacology is shared by several AMPAR channel blockers. Interestingly, PhTX-insensitive AMPARs failed to express in retinae from dark-reared animals demonstrating that light entering the eye triggers their expression. Eye-opening coincides with the consolidation of inhibitory cell connections suggesting that the developmental switch to a Ca2+-permeable AMPAR with novel pharmacology may be critical to synapse maturation in the mammalian retina.