Interactive reportRefinement of the ipsilateral retinocollicular projection is disrupted in double endothelial and neuronal nitric oxide synthase gene knockout mice
Introduction
Nitric oxide (NO) has received considerable attention 3, 9, 18because it is able to diffuse freely across cellular membranes 25, 40and thus could serve as a retrograde signal during Hebbian-type synapse plasticity 17, 28, 40. In this role, NO is thought to signal to the presynaptic terminal that activity in that terminal has resulted in a post-synaptic response. In 1990, Gally, Montague, and colleagues 17, 28published their “NO hypothesis” proposing that NO could also operate as a volume signal during patterning of axonal connections in the developing brain. According to this hypothesis, postsynaptic activity results in release of NO. Synapses that fire in synchrony with the release of NO would be strengthened, while those with uncorrelated firing would be weakened. They proposed that such a mechanism could result in matching correct axonal arbors with their target neurons during activity dependent stages of synaptic development.
Despite the appeal of this hypothesis, evidence for a role for NO in the developing brain is conflicting. In the chick ipsilateral retinotectal projection (IRP), a projection which is normally eliminated during embryonic development, inhibition of nitric oxide synthase (NOS), NO's synthetic enzyme, partially rescues the ipsilateral projection until at least E17 41, 42. NOS inhibition also disrupts segregation of the `on' and `off' sublaminae of the ferret lateral geniculate nucleus (LGN) during the first 6 weeks of life 6, 8. Inhibition of NOS does not, however, alter the plasticity in ocular dominance columns of visual cortex that occurs when imbalance is introduced by monocular deprivation 15, 31, 34nor does it block the development of eye specific lamination in the ferret LGN [8].
The rodent IRP offers another model system in which to study the role of NO in pathway development. Shortly after birth, both ipsilateral and contralateral retinal axons are distributed throughout much of the superior colliculus (SC) with many axons in both pathways misdirected to inappropriate targets 20, 26, 36. Both projections then undergo a refinement process in which the inappropriately located axons disappear. For the contralateral projection, this refinement is complete by P10–P12 30, 36. The ipsilateral projection undergoes a more prolonged refinement during which it first retracts into patches within the rostral and medial regions of SC and then becomes restricted to the medial SC [20]. Nitric oxide synthase (NOS) is expressed in retinorecipient neurons of the superficial gray layer of mouse SC during this period of refinement [35], suggesting that NO plays a role in this process. Nevertheless, we and others have been unable to detect any alterations to this refinement process in transgenic mice in which the gene for the neuronal isoform of NOS was disrupted 16, 43. Here we report that the refinement of the ipsilateral retinocollicular pathway is significantly disrupted in transgenic mice in which genes for both the endothelial and neuronal isoforms of NOS have been disrupted.
Section snippets
Animals
Double edothelial and neuronal isoforms of nitric oxide synthase (e, nNOS) homozygote knockout mouse [38]breeding pairs were initially received from Drs. Paul L. Huang and Mark C. Fishman of Massachusetts General Hospital, Harvard University. These animals were obtained by mating nNOS and eNOS mutant mice to produce double heterozygote mutants, and thus producing the homozygotes by breeding these heterozygote mutants. Normal C57-BL/6 mice obtained from Harlan Sprague–Dawley (Indianapolis, IN,
Refinement of the IRP in normal mice
In normal C57-BL/6 mice, by P15, the ipsilateral projection innervates only the most medial and rostral regions of the SC [20]. This pattern is further refined between P21–28 (Fig. 4). By P21, there are fewer patches of label in the rostral SC There is even less rostral label at P28, and the projection is confined largely to the medial edge of SC by P42 and in adult animals (Fig. 4).
Disruption of the ipsilateral projection in e, nNOS double knockout mice
Fig. 1 shows the distribution of the ipsilateral and contralateral retinocollicular pathway labeling in a P21
Discussion
A role for nitric oxide in developmental refinement of axonal projections in the visual system has been shown in only two other species. The chick IRP, which is eliminated during development in normal animals, is partially spared in animals treated with the NOS inhibitor n-ω-l-nitro-l-arginine between E8–E16 [42]. About 20% of the ipsilateral projection persisted at late embryonic stages, a sparing which was also dependent upon NMDA receptor activation [13]. Segregation of `on' and `off'
Acknowledgements
We thank Dr. William Johnson for assistance with the statistical analysis and Dr. Steven McLoon for his critical reading of the manuscript. This work was supported in part by the U.S. Public Health Service National Institutes of Health Grants NS-36000 and EY-02973 and a Louisiana Education Quality Support Fund (LEQSF) Enhancement Grant 1994-1995-ENH-TR-20 from the Board of Regents, State of Louisiana. Deborah Shuman was a Howard Hughes Foundation undergraduate research intern from the
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2009, Brain ResearchCitation Excerpt :NO also seems to function as a retrograde messenger during the formation of synaptic connections during early development. Studies in primary retino-recipient structures, including ferret thalamus, rat and mouse superior colliculus, and chick optic tectum, have shown that blockade of NO disrupts the process of retinal axon segregation (Cramer et al., 1996; Ernst et al., 1999, 2000; Campello-Costa et al., 2000; Vercelli et al., 2000; Wu et al., 2000a,b, 2001). In ferret thalamus, eye-specific segregation is not affected but a secondary process of on–off sublimation is disrupted.
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2007, Brain Research ReviewsCitation Excerpt :Similar results were described in studies using double eNOS and nNOS gene knockout mice. They have shown that the developmental refinement of the ipsilateral projections is significantly delayed in these mutant mice but that it occurs eventually, since the normal pattern of distribution of these projections throughout the superficial layers of the SC can be observed at adulthood (Wu et al., 2000a,b). Interestingly, not only the synthesis of NO by nNOS, amply expressed by collicular neurons, but also the synthesis by the eNOS isoform is involved, since in nNOS gene knockout mice no change in the refinement of the ipsilateral projections was observed (Mize et al., 1998).
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