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

The development of the ipsilateral retinocollicular pathway involves activi ty-dependent refinement in which misdirected axons retract to form a precis e retinotopic map in adults. This refinement is altered by disruption of ge nes for the endothelial and neuronal isoforms of nitric oxide synthase (e,n NOS), but the extent of disruption during early development is not known. T herefore, 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 we re injected into one eye to localize the ipsilateral retinal projection (IR P) within the superior colliculus (SC). At P4, the IRP in normal mice was d istributed throughout the dorsoventral extent of the superficial gray layer (SGL) across most of the rostrocaudal axis of SC. Between P4 and P9, the p athway 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 mu m. Refinement also began to occur between P4 and P9 in e,nNOS do uble knockout mice, but labeling was more extensive in P9, P15, and P21 kno ckout animals. This delay in refinement was confirmed quantitatively at P15 where differences in the area occupied by the pathway were statistically s ignificant. 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 ear ly ages, and the process of refinement more protracted than has been previo usly reported, suggesting that there is a prolonged critical period of syna ptic plasticity. J. Comp. Neurol. 426: 651-665, 2000. (C) 2000 Wiley-Liss, Inc.