SEROTONIN DEPLETION DURING SYNAPTOGENESIS LEADS TO DECREASED SYNAPTICDENSITY AND LEARNING-DEFICITS IN THE ADULT-RAT - A POSSIBLE MODEL OF NEURODEVELOPMENTAL DISORDERS WITH COGNITIVE DEFICITS

Studies in the past have revealed serotonin to play a role in regulati ng the development and maturation of the mammalian brain, largely thro ugh the release of the astroglial protein S-100 beta. S-100 beta plays a role in neurite extension, microtubule and dendritic stabilization and regulation of the growth associated protein GAP-43, all of which a re key elements in the production of synapses. Depletion of serotonin, and thus of S-100 beta, during synaptogenesis should lead to a loss o f synapses and the behaviors dependent on those synapses. The current study was undertaken to test this hypothesis. In order to assess the i nfluence of serotonin we have looked at the synaptic density in the ad ult after depletion, by using immunodensitometry of synaptic markers ( synaptophysin and MAP-2) and by studying behaviors thought to be highl y dependent on synaptic plasticity and density. Male Sprague-Dawley ra ts were depleted of serotonin on postnatal days (PND) 10-20 by treatin g with the tryptophan hydroxylase inhibitor parachlorophenylalanine (P CPA; 100 mg/kg, s.c.). On PND's 30 and 62, animals were perfused for i mmunodensitometry. Littermates were used for behavioral testing. At PN D 55-62, the animals were tested in an interchangeable maze with olfac tory cues and in an eight-arm radial maze. Our results show a loss of both synaptic markers in the hippocampus on PND 30. At PND 62, the onl y remaining loss was of the dendritic marker MAP-2. The animals had de ficits in both behaviors tested, suggestive of spacial learning defici ts and of the failure to extinguish learned behaviors or to re-learn i n a new set. Our findings show the long-term consequences of interferi ng with the role of serotonin in brain development on the morphology a nd function of the adult brain. These findings may have implications f or human diseases, including schizophrenia, thought to be related to n eurodevelopmental insults such as malnutrition, hypoxia, viruses or in utero drug exposure. Moreover, they provide further insights into the functioning of serotonin and S-100 beta in development and aging.