Introduction process does depend upon impulse activity and can be

Brain Research 886 2000 15–32 www.elsevier.com locate bres Interactive report Nitric oxide, impulse activity, and neurotrophins in visual system 1 development R. Ranney Mize , Fu-Sun Lo Department of Cell Biology and Anatomy and The Neuroscience Center , Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA Accepted 31 July 2000 Abstract Topographic refinement of synaptic connections within the developing visual system involves a variety of molecules which interact with impulse activity in order to produce the precise retinotopic maps found in the adult brain. Nitric oxide NO has been implicated in this process, as have various growth factors. Within the subcortical visual system, we have recently shown that nitric oxide contributes to pathway refinement in the superior colliculus SC. Long-term potentiation LTP and long-term depression LTD are also expressed in SC during the time that this pathway undergoes refinement. The role of NO has been demonstrated by showing that refinement of ipsilateral fibers in the retinocollicular pathway is significantly delayed in gene knockout mice in which both the endothelial and neuronal 21 isoforms of nitric oxide synthase NOS have been disrupted. The effect also depends upon Ca channels because refinement of both the 21 ipsilateral retinocollicular and retinogeniculate pathways is disrupted in genetic mutants in which the b3 subunit of the Ca channel has been deleted. LTD may also be involved in this process, because the time course of its expression correlates with that of pathway 21 refinement and LTD magnitude is depressed by nitrendipine, an L-type Ca channel blocker. LTP is also expressed during early postnatal development in the LGN and SC and may contribute to synaptic stabilization. The role of neurotrophins in pathway refinement in the visual system is also reviewed.  2000 Elsevier Science B.V. All rights reserved. Theme : Development and regeneration Topic : Visual system Keywords : Pattern formation; Synapse specificity; Growth factor; Superior colliculus; Lateral geniculate nucleus; Visual cortex

1. Introduction process does depend upon impulse activity and can be

influenced by patterned visual experience as well. These The major visual centers of the mammalian brain later stages of refinement are also mediated by various contain precise retinotopic maps which represent an image growth factors and other signals, the result being the of the external world. These maps are established gradually formation of very precise synaptic connections that func- during pre- and postnatal development. The process occurs tion in the adult. These stages of visual system develop- in stages. Early in development a coarse map is formed in ment have been reviewed extensively which the major axes of representation between the retina [10,17,70,78,86,139]. and its subcortical targets are established. This stage is The later stages of synaptic plasticity which result in activity independent, but involves a variety of molecules precise matching of presynaptic axons with post-synaptic that control axon guidance. These coarse maps are further neurons are thought to involve one or more retrograde refined at later stages of development, and this later signals which ‘inform’ the presynaptic terminal that it has established an appropriate connection with the postsynaptic neuron. Although a retrograde message is probably re- 1 Published on the World Wide Web on 16 August 2000. quired for this process [8,14,147], candidates for this Corresponding author. Tel.: 11-504-568-4012 or 568-4011; fax: 11- message have only recently been identified. Cellular 504-568-4392. E-mail address : rmizelsuhsc.edu R.R. Mize. mechanisms of synaptic potentiation and depression have 0006-8993 00 – see front matter  2000 Elsevier Science B.V. All rights reserved. P I I : S 0 0 0 6 - 8 9 9 3 0 0 0 2 7 5 0 - 5 16 R also recently been shown to occur during the later stages of postnatal development the projections from the retina to pathway refinement in visual system development. This the SC are exuberant in that both the ipsilateral and article focuses upon several retrograde signals, notably contralateral retinal pathways overlap extensively with nitric oxide and the neurotrophins, that contribute to many axons misdirected to inappropriate targets pathway refinement in the visual pathways. We also review [38,42,68,69,95,117,141,143]. Both projections sub- evidence that long term potentiation LTP and long term sequently undergo refinement in which incorrectly targeted depression LTD are involved in the synaptic refinement axons disappear either due to retraction of axon branches process. or to elimination of the parent axon. This process of refinement is thought to be mediated by the NMDA receptor in both rodent SC [142] and in the optic tectum of 2. Nitric oxide and pathway refinement in the lower vertebrates [35,36].