Excess of serotonin (5-HT) alters the segregation of ipsilateral and contralateral retinal projections in monoamine oxidase A knock-out mice: Possible role of 5-HT uptake in retinal ganglion cells during development

Retinal ganglion cell (RGCs) project to the ipsilateral and contralateral s ides of the brain in the dorsal lateral geniculate nucleus (dLGN) and the s uperior colliculus (SC). Projections from both eyes are initially interming led until postnatal day 3 (P3) but segregate into eye-specific layers by P8 . We report that this segregation does not occur in monoamine oxidase A kno ck-out mice (MAOA-KO) that have elevated brain levels of serotonin (5-HT) a nd noradrenaline. The abnormal development of retinal projections can be re versed by inhibiting 5-HT synthesis from PO to P15. We found that in MAOA-K O mice, 5-HT accumulates in a subpopulation of RGCs and axons during embryo nic and early postnatal development. The RGCs do not synthesize 5-HT but re uptake the amine from the extracellular space. In both MAOA-KO and normal m ice, high-affinity uptake of 5-HT and serotonin transporter (SERT) immunore activity are observed in retinal axons from the optic cup to retinal termin al fields in the SC and dLGN, In the dLGN, transient SEPT labeling correspo nds predominantly to the ipsilateral retinal projection fields. We show tha t, in addition to SERT, developing RGCs also transiently express the vesicu lar monoamine transporter gene VMAT2: thus, retinal axons could store 5-HT in synaptic vesicles and possibly use it as a borrowed neurotransmitter, Fi nally we show that the 5-HT-1B receptor gene is expressed by RGCs throughou t the retina from E15 until adult life. Activation of this receptor is know n, from previous studies, to reduce retinotectal activity; thus 5-HT in exc ess could inhibit activity-dependent segregation mechanisms. A hypothesis i s proposed whereby, during normal development, localized SEPT expression co uld confer specific neurotransmission properties on a subset of RGCs and co uld be important in the fine-tuning of retinal projections.