Abstract
The β-chemokine Ccl5 and its receptors are constitutively expressed in neurons of the murine inner retina. Here, we examined the functional and structural significance of this constitutive Ccl5 signaling on retinal development. We compared outcomes of electrophysiology, ocular imaging and retinal morphology in wild-type mice (WT) and mice with Ccl5 deficiency (Ccl5-/-). Assessment of retinal structure by ocular coherence tomography and histology revealed slight thinning of the inner plexiform layer (IPL) and inner nuclear layer (INL) in Ccl5-/- mice, compared to WT (p < 0.01). Assessment of postnatal timepoints important for development of the INL (P7 and P10) revealed Ccl5-dependent alterations in the pattern and timing of apoptotic pruning. Morphological analyses of major inner retinal cell types in WT, Ccl5-/-, gustducingfp and gustducingfp/Ccl5-/- mice revealed Ccl5-dependent reduction in GNAT3 expression in rod bipolar cells as well as a displacement of their terminals from the IPL into the GCL. RGC dendritic organization and amacrine cell morphology in the IPL was similarly disorganized in Ccl5-/- mice. Examination of the intrinsic electrophysiological properties of RGCs revealed higher spontaneous activity in Ccl5-/- mice that was characterized by higher spiking frequency and a more depolarized resting potential. This hyperactive phenotype could be negated by current clamp and correlated with both membrane resistance and soma area. Overall, our findings identify Ccl5 signaling as a mediator of inner retinal circuitry during development of the murine retina. The apparent role of Ccl5 in retinal development further supports chemokines as trophic modulators of CNS development and function that extends far beyond the inflammatory contexts in which they were first characterized.
Highlights
The laminar structure of the retina is formed by timed waves of retinal progenitor cell production and migration that is mediated by numerous transcription factors driving early- and late-born cell types (Ohsawa and Kageyama, 2008; Agathocleous and Harris, 2009; Mattar and Cayouette, 2015)
We found that C-C motif chemokine ligand 5 (Ccl5) deficiency in Ccl5−/− mice results in thinning of the inner retina, the inner nuclear layer (INL)
Examination of the intrinsic electrophysiological properties of retinal ganglion cell (RGC) revealed higher spontaneous activity in Ccl5−/− mice that was characterized by higher spiking frequency and a more depolarized resting potential
Summary
The laminar structure of the retina is formed by timed waves of retinal progenitor cell production and migration that is mediated by numerous transcription factors driving early- and late-born cell types (Ohsawa and Kageyama, 2008; Agathocleous and Harris, 2009; Mattar and Cayouette, 2015). Further differentiation into subtypes of these cells is mediated by induction of additional factors (Reese and Keeley, 2016) These subtypes are defined by differences in expression of neurotransmitters, neurotransmitter receptors, and ion channel classes, i.e., metabotropic versus ionotropic channels (Brandstätter et al, 1998; Huang et al, 2003; Ghosh et al, 2004). It is the proper wiring between subtypes of these broad cell classifications that ensures proper encoding to photon stimuli in the retina from a graded glutamate potential to action potentials that can be interpreted by higher visual centers in the brain. While intrinsic factors mediating development and maturation of bipolar cells, amacrine cells and RGCs are well-documented, extrinsic factors that direct formation of circuits at this critical synapse are largely unknown (Morgan and Wong, 2005)
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