Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior

Abstract

The serotonin 1A receptor (5-HT1A) has a major role in modulating the effects of serotonin on mood and behavior. Previous studies have shown that knockout of 5-HT1A selectively in the raphe leads to higher levels of anxiety during adulthood. However, it remains unclear whether this phenotype is due to variation in receptor levels specifically during development or throughout life. To test the hypothesis that developmental sensitivity may underlie the effects of 5-HT1A on anxiety, we used an inducible transgenic system to selectively suppress 5-HT1A levels in serotonergic raphe neurons from post-natal days (P) 14 to P30, with a maximal reduction of 40% at P21 and return to regular levels by P30. This developmental decrease in receptor levels has long-lasting consequences, increasing anxiety and decreasing social investigation in adulthood. In addition, post-natal knockdown of autoreceptors leads to long-term increases in the excitability of serotonergic neurons, which may represent a mechanism underlying the effects of post-natal receptor variation on behavior later in life. Finally, we also examined the interplay between receptor variation and juvenile exposure to stress (applied from P14 to P21). Similar to receptor knockdown, juvenile exposure to stress led to increased anxiety phenotypes but did not exacerbate 5-HT1A knockdown-mediated anxiety levels. This work indicates that the effects of 5-HT1A autoreceptors on anxiety and social behaviors are developmentally mediated and suggests that natural variations in the expression of 5-HT1A may act during development to influence individual anxiety levels and contribute to susceptibility to anxiety disorders.

Adult AMPA GLUA1 Receptor Subunit Loss in 5-HT Neurons Results in a Specific Anxiety-Phenotype with Evidence for Dysregulation of 5-HT Neuronal Activity

“…The reduction in 5-HT 1A autoreceptor sensitivity noted in the electrophysiology experiments coupled with reduced 5-HT release would be expected to result in reduced autoinhibition and hence an increased net firing rate of 5-HT neurons. Although changes in 5-HT 1A autoreceptor function during development have been associated with increased anxiety behaviors, downregulation of 5-HT 1A autoreceptors in adulthood has been shown not to impact on anxiety measures (Donaldson et al, 2013;Richardson-Jones et al, 2011). As we used an inducible system to achieve Gria1 deletion in adult Gria1 5HT-/-mice, the 5-HT 1A autoreceptor desensitization/downregulation observed occurred during adulthood making it unlikely that 5-HT 1A autoreceptor alterations are responsible for the observed anxiety phenotype.…”

Genetic and early environmental influences on the serotonin system: consequences for brain development and risk for psychopathology

“…163 For instance, it has recently been shown that knockout of the 5-HT 1A autoreceptor in 5-HT raphe neur ons 14-30 days after birth (corresponding to early childhood) leads to long-lasting increases in anxiety, decreased social behaviours and subtle alterations in neuron physiology. 164 In humans, improvements in compounds that permit the visualization of 5-HT target molecules in the human brain have helped us to understand the expression of receptors or proteins in the human brain. Developments in genetic array technologies make it possible to identify new genes and carry out (epi)genetic analyses on a large-scale basis.…”

Abrogated Freud-1/Cc2d1a Repression of 5-HT1A Autoreceptors Induces Fluoxetine-Resistant Anxiety/Depression-Like Behavior

“…Brains were cryo-sectioned at a thickness of 25 μm and mounted sections were maintained at −80°C until processing. Mounted sections were processed for 125 I-MPPI (Perkin Elmer, Boston, MA) autoradiography as described (Donaldson et al, 2014;Luckhart et al, 2016). Sections were exposed to Kodak BioMax MR film (VWR) for 24 h. Films were digitized at 1200-dpi resolution using an Epson Perfection V500 Photo Scanner, and signal density was measured using the mean luminosity function in ImageJ (1.49).…”

“…1F, WT, 135.8±20.95; cFko, 27.50±6.538 cells/template; t test, DF=6, t=4.933 **p=0.0026). To further quantify the levels of 5-HT1A binding sites, autoradiography was performed using the selective 5-HT1A antagonist 125 I-MPPI (Donaldson et al, 2014) and revealed a significant >1.5-fold increase in 5-HT1A binding in the dorsal and median raphe nuclei of cF1ko vs. cF1wt mice), but similar levels of 5-HT1A binding in hippocampus ( Figure 1H) …”