SEROTONIN DEPLETION DURING SYNAPTOGENESIS LEADS TO DECREASED SYNAPTICDENSITY AND LEARNING-DEFICITS IN THE ADULT-RAT - A POSSIBLE MODEL OF NEURODEVELOPMENTAL DISORDERS WITH COGNITIVE DEFICITS
C. Mazer et al., SEROTONIN DEPLETION DURING SYNAPTOGENESIS LEADS TO DECREASED SYNAPTICDENSITY AND LEARNING-DEFICITS IN THE ADULT-RAT - A POSSIBLE MODEL OF NEURODEVELOPMENTAL DISORDERS WITH COGNITIVE DEFICITS, Brain research, 760(1-2), 1997, pp. 68-73
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.