Abstract
Abstract: :
Purpose: Our goal was to assess the excitatory behavior of remodeling neuronal arrays in retinal degenerations, after loss of all photoreceptor cells. Methods: Glutamate–gated channel activation was visualized as in vivo and in vitro AGB permeation and combined with computational molecular phenotyping (Marc and Jones 2002 J Neurosci 22: 413) in rodent models of inherited retinal degenerations (transgenic rdcl and natural rd mice, > PND 60–100) after complete loss of photoreceptors. Datasets were visualized as rgb and theme maps of classified cell types, thus reporting the excitation states of identified neuronal populations. Results: The mid–stage remodeling mouse retina is extremely active in the absence of photoreceptors, indicating that light–independent events generate endogenous glutamatergic signaling. There are remarkable deviations from the normal retina: Rod bipolar cells (BCs) are inactive, as are all rod pathway neurons. Since rod BCs in the rdcl mouse lack a glutamate signal, cation channels gated by the mGluR6 pathway should be open. They are not, consistent with loss of the channel activation path (Strettoi et al. and Varela et al. 2003 Vision Res). Some OFF cone BCs are moderately active, implying re–entrant signaling. Some ON cone BCs are extremely active, as are their target amacrine (AC) and ganglion (GC) cells. The mechanism of high ON cone BC activity is unknown. In early remodeling, most cone–pathway ACs and GCs are active without any BC activity, implying a cryptic source of glutamate receptor activation. We have new evidence that dopaminergic ACs have a glutamatergic rather than a GABAergic signature, and they may provide an excitatory drive. Advanced remodeling also triggers migration of neurons. Migrating GCs are quiescent and suppression of glutamate receptor expression may be a prerequisite or consequence of migration. Conclusions: Light–independent glutamate–drive persists in the retinas of rodents after total photoreceptor loss. Initially limited to ACs and GCs, the source of endogenous glutamatergic–drive is unknown but may arise from dopaminergic / glutamatergic ACs. Remodeling recruits some BCs to rejoin excitatory networks, probably as re–entrant loops. Advanced remodeling events such as migration seems to induce loss of glutamate receptor expression.
Keywords: retinal degenerations: cell biology • excitatory neurotransmitters • plasticity