Disruption of retinogeniculate afferent segregation by antagonists to NMDA receptors

Abstract

Afferent activity has an important role in the formation of connections in the developing mammalian visual system. But the extent to which the activity of target neurons shapes patterns of afferent termination and synaptic contact is not known. In the ferret's visual pathway, retinal ganglion cell axons from each eye segregate early in development into eye-specific laminae in the lateral geniculate nucleus (LGN). The dorsal laminae (termed laminae A and A1) then segregate further into inner and outer sublaminae that retain input from on-centre and off-centre retinal axons, respectively. Thus, individual retinogeniculate axons form terminal arbors within laminae A and A1 that are restricted to one inner or outer sublamina. We report here that blockade of N-methyl-D-aspartate (NMDA) receptors on LGN cells with specific antagonists during the period of sublamina formation prevents retinal afferents from segregating into 'On' and 'Off' sublaminae. Retinogeniculate axons have arbors that are not restricted appropriately, or are restricted in size but inappropriately positioned within the eye-specific laminae. NMDA receptor antagonists may specifically disrupt a mechanism by which LGN neurons detect correlated afferent and target activity, and have been shown to reduce retinogeniculate transmission more generally, causing LGN cells to have markedly reduced levels of activity. These results therefore indicate that the activity of postsynaptic cells can significantly influence the patterning of inputs and the structure of presynaptic afferents during development.

A Role for Nitric Oxide in the Development of the Ferret Retinogeniculate Projection

“…For each section, a line was drawn bisecting the A layer. The sublamination index (Hahm et al, 1991) was determined for each axon as the proportion of the axon arbor area in the half of the A layer containing the majority of that arbor; the sublamination index thus varied from 0.5 (no sublamination) to 1 (complete sublamination).…”

“…Sublamination of retinogeniculate afferents was assessed at the level of individual retinal ganglion cell axon arbors in animals treated systemically with 40 mg/kg/d L-NoArg or 40 mg/kg/d D-NAME from P14 to P21. Axon labeling and analysis of axon arbors were done at P21 according to the methods outlined in Hahm et al (1991), so that the effects of NOS blockade could be compared with the effects of NMDA receptor blockade. Ferrets were given an overdose (Ͼ100 mg/kg, i.p.)…”

“…The restriction of retinogeniculate axon arbors into eye-specific layers appears to depend on action potential activity (Shatz and Stryker, 1988) but does not require activation of NMDA receptors (Smetters et al, 1994). The formation of ON/OFF sublaminae is also activity-dependent and is disrupted by in vivo blockade of NMDA receptors (Hahm et al, 1991). To investigate a possible mechanism whereby blockade of postsynaptic NMDA receptors in the lateral geniculate nucleus (LGN) results in changes in the size and position of presynaptic axon arbors, we tested the role of the diffusible messenger nitric oxide (NO) in the development of the retinogeniculate pathway.…”

“…Postsynaptic NMDA receptors contribute significantly to retinogeniculate synaptic transmission (Sillito et al, 1990;Kwon et al, 1991;Esguerra et al, 1992;Ramoa and McCormick, 1994). NMDA receptor antagonists infused into the ferret LGN disrupt the pattern of sublamination of presynaptic retinogeniculate axons; retinal ganglion cell axon arbors are either abnormally large or are restricted in size but terminate in inappropriate locations within the LGN (Hahm et al, 1991). In rats, blockade of NMDA receptors in the superior colliculus leads to abnormal branching of retinocollicular axons (Simon et al, 1992).…”

“…Blockade of afferent activity with tetrodotoxin disrupts the formation of eye-specific layers in the cat retinogeniculate projection (Shatz and Stryker, 1988) and the formation of ON/OFF sublaminae in the ferret (Cramer and Sur, 1996). The formation of ON/OFF sublaminae requires NMDA receptor activation (Hahm et al, 1991) during the third postnatal week, whereas the formation of eye-specific layers during the first postnatal week does not (Smetters et al, 1994). The sequential segregation of retinogeniculate afferents into eye-specific layers in an NMDA receptorindependent manner and into ON/OFF sublayers in an NMDA receptor-dependent manner provides an opportunity to investigate how neuronal activity effects changes in synaptic connections in the LGN and how activity may be transduced via different biochemical pathways during different phases of development.…”