Dysregulation of Serotonin During Early Development Alters Interhemispheric Connectivity in Rodents

The serotonergic system is one of the earliest neurotransmitter systems present in the developing central nervous system. With its early emergence and influence on the brain, serotonin (5HT) plays an important role in brain development. Several studies demonstrated that 5HT regulates numerous developmental processes starting from neurogenesis to axon guidance and synapses formation. Previous works in our lab and others have shown that genetic and environmental alterations of brain 5HT levels during early development lead to numerous cellular, anatomical and behavioral abnormalities that resemble the pathological characteristics of Autism. Human imaging studies in autistic patients have highlighted a reduction in the size and shape of the corpus callosum (CC). Interestingly, our recent data also revealed a reduction of callosal connectivity and altered myelin formation following perinatal exposure to selective serotonin reuptake inhibitor (SSRI) citalopram (CTM). Since 5HT levels in the brain are largely regulated via reuptake into presynaptic terminals through the serotonin transporter (SERT) and degradation by monoamine oxidase A (MAO A) enzyme, the overall aim of this project was to further analyze the integrity of the interhemispheric connectivity in the rodent that has been exposed to CTM or through genetic manipulation of MAO A during critical periods of neural development.;To address these issues, male and female Long Evans rats pups were exposed to either saline or CTM (20 mg/Kg/day) from postnatal day 8 to 21 (PN8-21) and compared to a non-treated group (NT). In addition, two lines of MAO A deficit mice; the MOA A knock-out mice (MAO A KO) and the hypomorphic MAO ANeo mice, were also examined and compare to the wild type (WT). The corpus callosum (CC) and anterior commissure (AC) architectures were measured and compared. Furthermore, immunohistochemical staining for oligodendrocytes (OL) marker was also conducted. In particular, OL density of CC and AC were analyzed among the experimental groups using stereological approaches. In addition, anterograde and retrograde neuro-tracers were injected into one cortical hemisphere and the connectivity between two hemispheres was examined.;Our data revealed: 1) reduced CC thickness, especially in the rostral part, of CTM exposed rats compare to SAL and NT rats; 2) increased AC cross sectional area in male CTM exposed rats; 3) decreased OL density in both the CC and AC of CTM exposed male rats; 4) decreased interhemispheric axons were noted in the primary somatosensory cortex (S1) with incidences of mis-routing axons in the CTM exposed male rats; and finally 5) such changes were found more severely in males than females.;As for MAO A deficit mice, our data revealed; 1) reduced CC thickness, especially in the rostral part, of MAO A KO and MAO ANeo mice compare to WT; 2) increased AC cross sectional area in MAO AN Neo mice compare to MAO A KO and WT mice; 3) pathological changes in OL and decreased OL density in both the CC and AC of MAO A KO and MAO ANNeo mice compare to WT; and 4) decreased callosal connection in the MAO ANNeo mice, compared to MAO A KO and WT mice.;Our present findings suggest that 5HT plays an important role in brain network formation. Furthermore, both environmental and genetic factors affecting the 5HT levels lead to a long lasting alteration of interhemispheric connections. The current data further suggest a potential link between dysregulation of 5HT and Autism. Our present findings also provide an important and novel implication regarding the mis-wiring of interhemispheric connectivity often noted in autistic patients. Furthermore, the sex-specific effect of 5HT levels dysregulation could provide an explanation to the difference in prevalence of Autism between boys and girls.