The Role of Neuronal Connexins 36 and 45 in Shaping Spontaneous Firing Patterns in the Developing Retina

Abstract

Gap junction coupling synchronizes activity among neurons in adult neural circuits, but its role in coordinating activity during development is less known. The developing retina exhibits retinal waves - spontaneous depolarizations that propagate among retinal interneurons and drive retinal ganglion cells to fire correlated bursts of action potentials. During development, two connexin isoforms, connexin36 (Cx36) and Cx45, are expressed in bipolar cells and retinal ganglion cells (RGCs), and therefore provide a potential substrate for coordinating network activity. To determine whether gap junctions contribute to retinal waves, we compared spontaneous activity patterns using calcium imaging, whole-cell recording and multielectrode array recording in control, single knockout (ko) mice lacking Cx45 and double knockout (dko) mice lacking both isoforms. Wave frequency, propagation speed and bias in propagation direction were similar in Ctr, Cx36ko, Cx45ko and Cx36/45dko retinas. However, the spontaneous firing rate of individual retinal ganglion cells was elevated in Cx45ko retinas, similar to Cx36ko retinas (Hansen et al., 2005; Torborg and Feller, 2005), a phenotype that was more pronounced in Cx36/45dko retinas. As a result, spatial correlations, as assayed by nearest neighbor correlation and functional connectivity maps, were significantly altered. In addition, Cx36/45dko mice had reduced eye-specific segregation of retinogeniculate afferents. Together, these findings suggest that although Cx36 and Cx45 do not play a role in gross spatial and temporal propagation properties of retinal waves, they strongly modulate the firing pattern of individual RGCs, ensuring strongly correlated firing between nearby RGCs and normal patterning of retinogeniculate projections.

Intrinsically photosensitive ganglion cells contribute to plasticity in retinal wave circuits

“…Cx36 is the most abundant retinal connexin and couples most ganglion cells to other ganglion or amacrine cells (25). Although cx36KO mice have an increase in asynchronous firing in between retinal waves, they exhibit cholinergic retinal waves with propagation patterns that are indistinguishable from WT during the first postnatal week (24,26). We found that β2-cx36 dKO mice did not exhibit recovered retinal waves in either the dark or light ( Fig.…”

“…Correlation index curves showed no difference in the dark and light for both WT and β2KO mice. We next used these correlation indices to construct connectivity maps, which show connections between neurons with the highest correlation indices (26,27). In particular, this strategy has been used in the developing hippocampus to identify highly connected hub neurons, which repeatedly initiate activity (28).…”

“…The median correlation index was then plotted as a function of increasing intercellular distance. To establish connectivity maps, we defined two cells as being connected if their correlation index fell in the top 5% of all correlation index values (26). We then extracted cells that were connected to at least 15% of other cells (red units in Fig.…”

Bloqueio do acoplamento celular após trauma mecânico na retina altera a distribuição de células em apoptose.

“…(Fujihara et al, 2008;Kermer et al, 1999;Lynch, Dawson, 1994). Em relação à comunicação direta célula-célula, a concentração do cálcio parece ser particularmente importante, uma vez que é classicamente associado a apoptose no sistema nervoso, além disso, alterações rápidas na concentração de cálcio intracelular, causadas pelo acoplamento via JCs, foram claramente demonstrados na retina (Blankenship et al, 2011;Firth et al, 2005). A transferência de segundos mensageiros facilmente difusíveis por canais de JCs, como IP3, poderia controlar as concentrações de cálcio citosólico (Bosanac et al, 2002).…”

Caracterização de conexinas neuronais no desenvolvimento pós-natal do hipocampo de ratos.

“…Em retinas de camundongos KO para a Cx36 e Cx45, apesar de ser observado o aumento do número de potenciais de ação ocorridos de maneira desincronizada, não foi notado a extinção completo da atividade, demonstrando que as Cx45 e Cx36 não são necessárias para a propagação das ondas retinianas. Curiosamente, a restrição da expressão de apenas um dessas Cxs não altera de forma significativa os padrões de propagação das ondas da retina (Blankenship et al, 2011).…”