Lack of 5-HT 1B receptor and of serotonin transporter have different effects on the segregation of retinal axons in the lateral geniculate nucleus compared to the superior colliculus

Abstract

We have shown previously that raised levels of serotonin (5-hydroxytryptamine or 5-HT) during development prevent retinal ganglion cell axons from segregating into eye-specific regions in their principal targets: the superior colliculus and the dorsal lateral geniculate nucleus. Possible mediators of 5-HT in this system include its plasma membrane transporter, which is transiently expressed by a sub-population of retinal ganglion cells, and the presynaptic 5-HT 1B receptor carried on retinal ganglion cell axons. We analysed the retinal projections of 5-HT 1B knockout ( n=15), serotonin transporter knockout ( n=14), serotonin transporter/5-HT 1B double knockout ( n=4) and monoamine oxidase A/5-HT 1B double knockout ( n=3) mice. In all four different knockout mice, the ipsilateral retinal projection to the superior colliculus was more diffuse and lost its characteristic patchy distribution. The alterations were most severe in the serotonin transporter knockout mice, where the ipsilateral retinal fibres covered the entire rostrocaudal and mediolateral extent of the superior colliculus, whereas in the 5-HT 1B and double knockout mice, fibres retracted from the caudal and lateral superior colliculus. Abnormalities in the 5-HT 1B knockout mice appeared only after postnatal day (P) 4. Treatment with parachlorophenylalanine (at P1–P12) to decrease serotonin levels caused an exuberance of the ipsilateral retinal fibres throughout the superior colliculus ( n=9). In the dorsal lateral geniculate nucleus in contrast, the distribution and size of the ipsilateral retinal projection was normal in all four knockout mice. In the serotonin transporter knockout mice however, the contralateral retinal fibres failed to retract from the mediodorsal dorsal lateral geniculate nucleus, an abnormality that was reversed by early treatment with parachlorophenylalanine and in the serotonin transporter/5-HT 1B double knockout. Our observations indicate: (1) that the lack of 5-HT transporter and the associated changes in 5-HT levels impair the segregation of retinal axons in both the superior colliculus and the dorsal lateral geniculate nucleus; (2) that 5-HT and 5-HT 1B receptors are necessary for the normal refinement of the ipsilateral retinal fibres in the superior colliculus, but are not essential for the establishment of eye-specific segregation in the thalamus. Thus, both an excess and a lack of 5-HT affect the refinement of the superior colliculus retinal projection, while the establishment of eye-specific patterns in the dorsal lateral geniculate nucleus appears not to be sensitive to the lack of 5-HT or 5-HT 1B receptors.