apoptosis of inner retinal neurons, including rod bipolar cells and horizontal cells, does occur at late stages in the degenerative process (Strettoi and Pignatelli 2000; Gargini et al. 2007). It is critical to understand the timing and functional ramifications of these changes, since they may impact the choice and eventual success of treatment strategies. This review will discuss the evidence for functional alterations in the inner retina in animal models of retinal degeneration, with particular emphasis on neurons of the ‘through’ pathway, the bipolar and ganglion cells.

60.2 Bipolar Cell Function in Retinal Degeneration

Numerous strategies that show promise for the treatment of RP are contingent on the normal functioning of bipolar cells. For example, Maclaren et al. (2006) showed that photoreceptor precursor cells could be successfully transplanted and integrated into a degenerated mouse retina, however, the success of such an approach most likely relies on the normal functioning of bipolar cells at the time of transplantation. A detailed knowledge of the timing of bipolar cell functional changes would also be critical for appropriate design of retinal implants, targeting of gene-therapy to photoreceptors or the incorporation of photosensitive channels into bipolar cells themselves (Lagali et al. 2008). In this section, we will summarise what is known about the localisation and function of glutamate receptors on bipolar cells in the degenerating retina.

60.2.1Glutamate Receptors of Bipolar Cells in the Normal and Degenerating Retina

In darkness, glutamate is released from photoreceptors and activates glutamate receptors that are tightly localized to the dendritic tips of the bipolar cells. There are two functionally distinct types of bipolar cells that respond with opposite polarities depending on the type of glutamate receptors expressed. ON bipolar cells (including rod bipolar cells) express the sign-inverting metabotropic glutamate receptor, mGluR6 (Nakajima et al. 1993). Activation of this receptor activates a G-protein coupled cascade that leads to the closure of an as yet unidentified cation-permeable channel, thereby hyperpolarising the cell (Slaughter and Miller 1985). In contrast, OFF cone bipolar cells express sign-conserving ionotropic glutamate receptors of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate type that are depolarised in response to glutamate.

Alterations in the localisation and expression of mGluR6 receptors have been described in a variety of animal models of retinal degeneration using immunohistochemistry. In mouse models such as the rd1 (Strettoi and Pignatelli 2000), rd10 (Gargini et al. 2007; Puthussery et al. 2009; Barhoum et al. 2008) and crx knockout (Pignatelli et al. 2004), there is evidence for progressive down-regulation