Normal development of the ipsilateral retinocollicular pathway and its disruption in double endothelial and neuronal nitric oxide synthase gene knockout mice

Abstract

The development of the ipsilateral retinocollicular pathway involves activity-dependent refinement in which misdirected axons retract to form a precise retinotopic map in adults. This refinement is altered by disruption of genes for the endothelial and neuronal isoforms of nitric oxide synthase (e,nNOS), but the extent of disruption during early development is not known. Therefore, we studied the refinement of this pathway in normal C57/BL6 and e,nNOS double knockouts from P4 to P21 and in adults. Anterograde tracers were injected into one eye to localize the ipsilateral retinal projection (IRP) within the superior colliculus (SC). At P4, the IRP in normal mice was distributed throughout the dorsoventral extent of the superficial gray layer (SGL) across most of the rostrocaudal axis of SC. Between P4 and P9, the pathway retracted to the rostromedial SC, and retracted further between P15 and P21, such that multiple patches of label were seen only in the rostral 200-300 microm. Refinement also began to occur between P4 and P9 in e,nNOS double knockout mice, but labeling was more extensive in P9, P15, and P21 knockout animals. This delay in refinement was confirmed quantitatively at P15 where differences in the area occupied by the pathway were statistically significant. The refinement process is therefore in progress in both normal and e,nNOS knockout mice before eye opening but is significantly delayed in the double knockouts. The IRP in normal mice is also more exuberant at early ages, and the process of refinement more protracted than has been previously reported, suggesting that there is a prolonged critical period of synaptic plasticity.

Synapse maturation is enhanced in the binocular region of the retinocollicular map prior to eye opening

“…1G): 1) P3-4, when functional contacts from the retina to the colliculus have already formed but inputs from the two eyes are mixed in the SGS layer of the binocular SC (Godement et al 1984;Wu et al 2000); 2) P6 -7, when inputs from the two eyes are mostly segregated into their corresponding layers; and 3) P12-13, shortly before eye opening and the onset of visual experience. Binocular interactions are likely to be most prominent in the antero-medial SC during the first postnatal week, when inputs from the two eyes are mixed in the SGS.…”

“…We focus here on visual map development in the mouse SC because of the relatively precocious maturation of this map and its simple spatial organization (Godement et al 1984;Grantyn et al 2004;Mize and Salt 2004;Simon and O'Leary 1992;Wu et al 2000). Retinal inputs from both eyes are present in the SC at birth, and by the time of eye opening [around postnatal day (P)14] the anatomical development of the visual map is virtually complete (Dhande et al 2011;Godement et al 1984).…”

Effects of trkB knockout on topography and ocular segregation of uncrossed retinal projections

“…Serotonin (Upton et al 1999), nitric oxide (Vercelli et al 2000; Wu et al 2000), calcium influx (Cork et al 2001) and adenylate cyclase (Ravary et al 2003) have all been implicated in ocular segregation and may mediate the effects of electrical activity on this organizational feature of retinal projections.…”

Activity dependent mechanisms of visual map formation - From retinal waves to molecular regulators

“…The developmental sequence is somewhat similar in the SC, with a progressive elimination of ipsilateral inputs in the most superficial layers, although ipsilateral axons do not invade completely the SGS even before P3, and are mainly eliminated by P8 [14,16]. Thus, in the SC, the overlap of ipsilateral and contralateral retinal inputs is not as important as in the dLGN possibly because other molecular factors set up a laminar organization in parallel to the segregation of ipsilateral and contralateral axons, preventing a complete overlap.…”

“…Pharmacological inhibition of calcium sensitive nitric oxide synthase (NOS) in ferrets did not impair eye specific segregation dLGN [93]. In contrast, genetic approaches of NOS inhibition leads to ectopic ipsilateral projection caudally in the SC of NOS KO mice [16] and in the SC of NOS inhibitor treated rats [94], but without clear defects in eye specific segregation.…”