Comparison in Serotonin Receptor 1A and 2A expressions along the antero-posterior axis of human hippocampus in Major Depressed patients with and without medications and psychiatrically healthy controls, and Serotonin Receptor 4 expression pattern analysis

Major Depressive Disorder, often referred as Major Depression, is the second cause of death in people aged between 19 and 25-years-old, but despite the increasing awareness, the molecular mechanisms of depression are still poorly understood. Since Major Depression can affect hippocampal structures, and since antidepressants treatment involving increasing amount of serotonin in synaptic cleft due to the blockage of serotonin reuptake, as the action exerted by the first-line antidepressant Selective Serotonin Reuptake Inhibitor, can reverse depressive affection, serotonin receptors have been highlighted as mediator of serotonin role in depressive pathogenesis and etiology. Particularly, the expression patterns of Serotonin Receptor 1A (5-HT1A), 2A (5-HT2A) and 4 (5-HT4), widely reported to be most likely involved in Major Depression and suicide pathophysiology, have been studied in human hippocampal sections, collected post-mortem from unmedicated and SSRIs-medicated subjects with Major Depressive Disorder, and compared to age- and gender-matched psychiatrically healthy controls. Each serotonin receptor expression has been localized on the hippocampal sections using specific [35S]-radiolabeled riboprobe, and it has been quantified by using Densita software for autoradiographic quantification. 5-HT4 expression has been detected in human hippocampus for the first time, and together with 5-HT1A show an evolutionary preserved expression pattern in mammal hippocampus, and an apparent co-localization with 5-HT1A in Dentate Gyrus, while 5-HT2A displays a neat expression in human Dentate Gyrus, that has not been observed in rodent and primate ones. 5-HT1A and 5-HT2A expressions in human hippocampus have been analized along the antero-posterior axis, with significant p-values for 5-HT1A expression gradient but low R2 values in psychiatrically healthy controls and SSRIs-medicated subjects in Dentate Gyrus (respectively, p=0.0412, R2=0.1924; p=0.000266, R2=0.4397), in Cornu Ammonis 3 (respectively, p=0.0287, R2=0.0971; , p=0.00959, R2=0.3699) and in Cornu Ammonis 1 (respectively, p=0.0353, R2= 0.203; p=0.0144, R2=0.2641), while subjects 5-HT2A antero-posterior expression doesn’t have any peculiar p-value or R2 value. Age of SSRIs-medicated subjects has some inference on 5-HT1A expression in anterior (p=0.0436; R2=0.6828) and mid (p=0.0301; R2=0.8597) Dentate Gyrus, while the affection on 5-HT2A expression by Age is clearly present in psychiatrically healthy controls in anterior (p=0.0301; R2=0.7044) and mid (p=0.00996; R2=0.8913) Dentate Gyrus and in anterior (p=0.00158; R2=0.9461) Cornu Ammonis 1. Since not all the samples have a normal distribution, comparisons of 5-HT1A and 5-HT2A expression between controls and unmedicated and medicated depressed subjects have been analyzed using, side-by-side, a parametric and a non-parametric statistical analysis, considering also the Age factor as a covariate: Kruskall-Wallis (non-parametric) test has highlighted significant or close-to-significativity p-values in anterior Dentate Gyrus (p=0.06475) and anterior Cornu Ammonis 3 (p=0.04952) only for 5-HT2A expression, while One-Way Anova with Age as covariate as found significant comparisons in anterior (p=0.0391) and mid (p=0.024) Dentate Gyrus for 5-HT1A expression, and significant comparisons in anterior Dentate Gyrus (p=0.0044), anterior Cornu Ammonis 3 (p=0.00644) and anterior Cornu Ammonis 1 (p=0.0181). Even considering the strongest limitation of this study, which is the small number of available subjects, observing neat differences in 5-HT1A and 5-HT2A expressions between younger controls, SSRIs-medicated and unmedicated major depressed subjects is still possible. These data may suggest a major sensitivity of younger subjects to mood disorders