Abstract
AII amacrine cells are essential interneurons of the primary rod pathway and transmit rod-driven signals to ON cone bipolar cells to enable scotopic vision. Gap junctions made of connexin36 (Cx36) mediate electrical coupling among AII cells and between AII cells and ON cone bipolar cells. These gap junctions underlie a remarkable degree of plasticity and are modulated by different signaling cascades. In particular, Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been characterized as an important regulator of Cx36, capable of potentiating electrical coupling in AII cells. However, it is unclear which CaMKII isoform mediates this effect. To obtain a more detailed understanding of the isoform composition of CaMKII at retinal gap junctions, we analyzed the retinal distribution of all four CaMKII isoforms using confocal microscopy. These experiments revealed a differential distribution of CaMKII isoforms: CaMKII-α was strongly expressed in starburst amacrine cells, which are known to lack electrical coupling. CaMKII-β was abundant in OFF bipolar cells, which form electrical synapses in the outer and the inner retina. CaMKII-γ was diffusely distributed across the entire retina and could not be assigned to a specific cell type. CaMKII-δ labeling was evident in bipolar and AII amacrine cells, which contain the majority of Cx36-immunoreactive puncta in the inner retina. We double-labeled retinas for Cx36 and the four CaMKII isoforms and revealed that the composition of the CaMKII enzyme differs between gap junctions in the outer and the inner retina: in the outer retina, only CaMKII-β colocalized with Cx36-containing gap junctions, whereas in the inner retina, CaMKII-β and -δ colocalized with Cx36. This finding suggests that gap junctions in the inner and the outer retina may be regulated differently although they both contain the same connexin. Taken together, our study identifies CaMKII-β and -δ as Cx36-specific regulators in the mouse retina with CaMKII-δ regulating the primary rod pathway.
Highlights
Electrical synaptic transmission allows fast propagation of electrical impulses, cell synchronization and network oscillations (Hormuzdi et al, 2001; Christie et al, 2005)
Our data point to a variable subunit composition, as calmodulin-dependent kinase II (CaMKII)-β predominated at electrical synapses in the outer retina whereas CaMKII-δ was the predominant subunit to associate with Cx36 in AII and TH2 amacrine cells in the inner retina
As shown before in many different brain regions (Lisman et al, 2002), CaMKII-β is located in the retina at the postsynaptic side of glutamatergic synapses; in contrast, we detected CaMKII-δ inside the glutamatergic bipolar cell terminals, suggesting that the different isoforms fulfill different functions in the retina
Summary
Electrical synaptic transmission allows fast propagation of electrical impulses, cell synchronization and network oscillations (Hormuzdi et al, 2001; Christie et al, 2005) It relies on specialized cell-cell contacts called gap junctions, which are formed by connexin proteins. Recent evidence indicates that the efficacy of these synapses is dynamically regulated by neuromodulators and interaction with glutamatergic synapses (reviewed in Pereda et al, 2013) Both regulatory pathways activate signaling cascades that change the phosphorylation state of the underlying connexin protein. The electrical synapses formed by the AII amacrine cells are highly dynamic and coupling changes with different levels of background illumination (Bloomfield and Völgyi, 2004), with low coupling in darkness and under photopic conditions and strong coupling at higher scotopic light levels. In AII cells, CaMKII potentiates Cx36 coupling in an activity-dependent manner
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