193. INCREASED SENSITIVITY OF CENTRAL SEROTONERGIC NEURONS TO CORTICOSTEROIDS FOLLOWING MATERNAL IMMUNE ACTIVATION: SIGNIFICANCE FOR MOOD DISORDERS

Abstract Background In our previous study (Csatlosova et al Eur Neuropsychopharmacol 43:82, 2021), we found that maternal immune activation (MIA) with lipopolysaccharide (LPS) led to decreased excitability of 5-HT neurons in the offspring’ DRN. It may explain increased anxiety (Enayati et al Brain Res Bull 87:295, 2012) and depressive-like behavior (Lin and Wang Behav Brain Res 259:24, 2014) in the offspring of MIA dams. Since MIA leads to increased glucocorticoid signaling in the offspring (Zager et al Neuroimmunomodulation 21:37, 2014), and since glucocorticoids inhibit 5-HT neurons (Wang et al J Physiol 590:5795, 2012), we suggested that decreased 5-HT neuronal firing activity in the offspring of MIA rats might result from abnormal glucocorticoids-5-HT interaction. The present study aimed to test this hypothesis. Aims & Objectives The present study aimed to examine the effect of the glucocorticoids receptor agonist dexamethasone on the excitability of DRN 5-HT neurons in the offspring of control and MIA rats. Method Adult female and male Wistar rats were placed in cages with one male and three females in each. Vaginal smears were taken daily, and the day sperm cells were detected was considered as day zero of gestation. During days 15-19 of the gestation, dams were subcutaneously (s.c.) administered LPS at increasing doses of 20, 20, 40, 40, and 80 μg/kg. Control dams were injected with saline. In vivo electrophysiological experiments were performed in male and female offspring reaching the age of two months. Animals were anesthetized by chloral hydrate and glass electrodes were stereotaxically inserted to the dorsal raphe nucleus (DRN). Spontaneously active 5-HT neurons were and identified by the waveform of their action potentials and pattern of their generation. After a basal activity of a neuron was recorded for at least one minute, dexamethasone-cyclodextrin complex was administered intravenously (i.v.), in cumulative doses of 1-5 mg/kg. The firing activity of the neurons after dexamethasone administration was expressed as mean ± standard error of mean (SEM) of their basal activity. Two-way analysis of variance for repeated measures (RM ANOVA), followed by Bonferroni post-hoc test, was used to examine the effects of maternal LPS and dexamethasone. Results Dexamethasone dose-dependently inhibited 5-HT neurons. This inhibition was stronger in the offspring of the MIA dams, reaching the maximum (after the administration of 5 mg/kg of dexamethasone) of 2±2% of baseline in males and 25±12% of baseline in females, comparing to the offspring of control dams (62±17 and 70±30%, respectively). In both sexes, significant effect of dexamethasone was detected (p<0.001 in males and p<0.01 in females, RM ANOVA). Bonferroni post-hoc test revealed significant (p<0.01, comparing to the baseline) inhibition of 5-HT neuronal firing activity after 1-5 mg of dexamethasone in male and 3-5 mg of dexamethasone in female offspring of the MIA dams. Significant differences in the excitability of 5-HT neurons between the offspring of control and MIA dams were observed after the injection of 5 mg/kg of dexamethasone in males and 3 mg/kg in females. Discussion & Conclusions The results of the current study suggest that MIA increases the sensitivity of the offspring 5-HT neurons to corticosteroids. This work was supported by the grants APVV-20-0202, APVV-22-0061, VEGA-2/0057/22, and VEGA-2/0045/24.