Abstract
Fetal alcohol exposure has been associated with many neuropsychiatric disorders that have been linked to altered serotonin (5-hydroxytryptamine; 5-HT) signaling, including depression and anxiety. During the first 2 weeks of postnatal life in rodents (equivalent to the third trimester of human pregnancy) 5-HT neurons undergo significant functional maturation and their axons reach target regions in the forebrain (e.g., cortex and hippocampus). The objective of this study was to identify the effects of third trimester ethanol (EtOH) exposure on hippocampal 5-HT signaling. Using EtOH vapor inhalation chambers, we exposed rat pups to EtOH for 4 h/day from postnatal day (P) 2 to P12. The average serum EtOH concentration in the pups was 0.13 ± 0.04 g/dl (legal intoxication limit in humans = 0.08 g/dl). We used brain slices to assess the modulatory actions of 5-HT on field excitatory postsynaptic potentials in the hippocampal CA3 region at P13-P15. Application of the GABAA/glycine receptor antagonist, picrotoxin, caused broadening of field excitatory postsynaptic potentials (fEPSPs), an effect that was reversed by application of 5-HT in slices from air exposed rats. However, this effect of 5-HT was absent in EtOH exposed animals. In slices from naïve animals, application of a 5-HT1A receptor antagonist blocked the effect of 5-HT on the fEPSPs recorded in presence of picrotoxin, suggesting that third trimester ethanol exposure acts by inhibiting the function of these receptors. Studies indicate that 5-HT1A receptors play a critical role in the development of hippocampal circuits. Therefore, inhibition of these receptors by third trimester ethanol exposure could contribute to the pathophysiology of fetal alcohol spectrum disorders.
Highlights
The hippocampal formation plays a central role in learning and memory processes (Ranganath, 2010; Buzsaki and Moser, 2013)
We exposed the slices to the GABAA/glycine receptor antagonist, picrotoxin (PTX), which resulted in widening of the field excitatory postsynaptic potentials (fEPSPs) (Figures 2A,B)
The application of PTX significantly increased the fEPSP A.U.C. (repeated measures one-way ANOVA F(3, 21) = 21.67, P = 0.0001; Holm-Sidak’s post-hoc test = P < 0.05 at 2–4 vs. 6–8 min); addition of the NMDA receptor antagonist, APV (100 μM) did not have a significant effect on the fEPSP recorded in PTX (Holm-Sidak’s post-hoc test P > 0.05 at 6–8 vs. 12–14 min; Figures 2A,B), suggesting that PTX does not broaden the fEPSP by activating NMDA receptors via membrane potential depolarization and removal of Mg2+ block
Summary
The hippocampal formation plays a central role in learning and memory processes (Ranganath, 2010; Buzsaki and Moser, 2013). A critical period for hippocampal development is the third trimester of human pregnancy (equivalent to the first 1–2 weeks of postnatal life in rodents). The number of synapses dramatically increases during this period and spontaneous activity drives the formation and early refinement of hippocampal neuronal networks (Mohajerani and Cherubini, 2006; Lohmann and Kessels, 2014). The elevation in 5-HT levels is a consequence of a dramatic increase in innervation of the hippocampus by serotoninergic axonal terminals originating in the dorsal raphe nucleus (Lidov and Molliver, 1982). 5-HT neurons in the developing dorsal raphe nucleus undergo significant functional changes during the third trimester equivalent (Rood et al, 2014; Morton et al, 2015). The 5-HT neurotransmitter system is actively refined during this developmental period, making it potentially susceptible to a number of insults
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