Neonatal serotonin depletion alters behavioral responses to spatial change and novelty

Abstract

Multiple brain disorders that show serotonergic imbalances have a developmental onset. Experimental models indicate a role for serotonin as a morphogen in brain development. To selectively study the effects of serotonin depletions on cortical structural development and subsequent behavior, we developed a mouse model in which a serotonin neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), is injected into the medial forebrain bundle (mfb) on the day of birth. Littermates with saline injections into the mfb and age matched mice served as controls. This study characterized the extent and duration of serotonergic denervation after the selective neonatal lesion and investigated effects on exploratory behavior, spatial learning and anxiety in mice of both sexes. We report significant decreases in the serotonergic (5-HT) innervation to cortex and hippocampus, but not to subcortical forebrain structures in 5,7-DHT-lesioned mice. The depletion of 5-HT fibers in cortical areas was long lasting in lesioned mice but autoradiographic binding to high affinity 5-HT transporters was only transiently reduced. Male but not female lesioned mice reduced their exploration significantly in response to spatial rearrangement and object novelty, suggesting increased anxiety in response to change but normal spatial cognition. Our data show that developmental disruptions in the serotonergic innervation of cortex and hippocampus are sufficient to induce permanent, sex specific, behavioral alterations. These results may have significant implications for understanding brain disorders presenting with cortical morphogenetic abnormalities and altered serotonin neurotransmission, such as autism, schizophrenia and affective disorders.

Modeling early cortical serotonergic deficits in autism

“…Similarly, at PND 90, the lesioned mice showed robust increases in the width of all cortical layers, with different layers affected to a different extent in males and females [60]. However, at approximately one year of age, only layer IV was still significantly increased in width and overall cortical size was no longer different from controls [61]. Moreover, our recent preliminary data suggests that substantial cortical volume increases exist as early as PND 7 (unpublished observations).…”

“…However, this discrepancy could be explained by a post-lesion increase in serotonin transporter sites beginning with adolescence. Our autoradiographic study of SERT sites showed that the density of SERT sites in 5,7-DHT-treated mice was reduced in both cortex and hippocampus until PND 15 [61]. However, at PND 30 the 5,7-DHT-lesioned mice showed an increased density of uptake sites as compared with age normal controls but not with vehicleinjected animals.…”

“…As described in Hohmann et al [60,61], quantitative morphological assessments were performed on 50 μm coronal sections that were stained with Methylene BlueAzure II (Sigma-Aldrich). Briefly, using the MCID, AIS imaging system (Imaging Research, Inc., St. Catherine's, Ontario) images of the tissue were digitized and cortical width was measured at two separate levels through the anterior and posterior somatosensory cortex.…”

Prenatal SSRI Use and Offspring With Autism Spectrum Disorder or Developmental Delay

“…Serotonergic function is influenced by sex hormones, 26,27 and serotonin system biological variations by gender have been reported. 28 Mice pups prenatally exposed to agents that can alter serotonergic function, including an SSRI, 29,30 showed permanent sex-specific changes in behavior. Moreover, in children exposed prenatally to antidepressants, delays in motor milestones were greater in boys.…”

Perinatal antidepressant exposure alters cortical network function in rodents

“…Interestingly, these findings were obtained from male rats, in partial support of the notion that male subjects may be more vulnerable to disruptions of the 5-HT system than their female counterparts are, just as males are more likely to exhibit signs of ASD over females. In line with this view, recent reports have suggested that male pups have a much higher 5-HT level (showing a prominent peak at P3) compared with female pups (displaying a more gradual elevation at P5) (30), and depletion of 5-HT with the neurotoxin 5,7-dihydroxytryptamine in male mice on P1 preferentially affects spatial rearrangement and performance in object-novelty behavioral tests, i.e., evaluations of behavioral traits that are often implicated in ASD (31). At present, several obvious questions that have yet to be addressed are whether perinatal treatment with SSRIs produces ASD-like behavior in rodents, whether this type of drug exposure has the potential to alter corticocortical network function, and whether this treatment affects female pups to a similar degree.…”