Allopregnanolone Prevents Dieldrin-Induced NMDA Receptor Internalization and Neurotoxicity by Preserving GABAA Receptor Function

Abstract

Dieldrin is an endocrine disruptor that accumulates in mammalian adipose tissue and brain. It induces convulsions due to its antagonism of the γ-aminobutyric acid A receptor (GABA(A)R). We have previously reported that long-term exposure to dieldrin causes the internalization of the N-methyl-D-aspartate receptor (NMDAR) as a result of persistent GABA(A)R inhibition. Because the neurosteroids 17β-estradiol (E2) and allopregnanolone are known to modulate the function and trafficking of GABA(A)R and NMDAR, we examined the effects of E2 and allopregnanolone on dieldrin-induced GABA(A)R inhibition, NMDAR internalization, and neuronal death in cortical neurons. We found that 1 nM E2 increased the membrane expression of NR1/NR2B receptors and postsynaptic density 95 but did not induce their physical association. In contrast, 10 nM E2 had no effect on these proteins but reduced NR2A membrane expression. We also found that exposure to 60 nM dieldrin for 6 d in vitro caused the internalization of NR1 and NR2B but not NR2A. Treatment with either 1 nM E2 or 10 μM allopregnanolone prevented the dieldrin-induced reduction in membrane levels of the NR1/NR2B receptors. Furthermore, prolonged exposure to 200 nM dieldrin down-regulated the expression of NR2A; this was inhibited only by allopregnanolone. Although both hormones restored NMDAR function, as measured by the NMDA-induced rise in intracellular calcium, allopregnanolone (but not E2) reversed the inhibition of GABA(A)R and neuronal death caused by prolonged exposure to dieldrin. Our results indicate that allopregnanolone protects cortical neurons against the neurotoxicity caused by long-term exposure to dieldrin by maintaining GABA(A)R and NMDAR functionality.

Estrogen Regulates Protein Synthesis and Actin Polymerization in Hippocampal Neurons through Different Molecular Mechanisms

“…Therefore, it is possible that activation of Rac/PAK, as opposed to RhoA/ROCK, has not yet completely developed in adolescent rats. It is also widely acknowledged that estradiol exhibits a biphasic dose–response for some of its non-genomic and genomic actions (54, 55). In particular, estradiol was found to increase Rac/Cdc42 activity at the same concentration used in our study (12, 13).…”

Calpain-1 and Calpain-2: The Yin and Yang of Synaptic Plasticity and Neurodegeneration

“…In contrast, calpain-2 was not associated with this complex under basal conditions or recruited by activity, consistent with the absence of calpain-2 activation following synaptic NMDAR activation. Besides the extrasynaptic NMDAR-STEP pathway, it has been reported that SAP102 mediates the movement of NR2B-containing NMDARs from synaptic to extrasynaptic membranes [80], where calpain has been shown to cleave NR2B and disrupt its interaction with SAP102 under neurotoxic conditions [81]. As indicated in Box 1, calpain-1 and calpain-2 exhibit different types of PDZ binding motifs, and it is therefore likely that these different binding sites are involved in the different scaffolding of calpain-1 and calpain-2 to distinct protein clusters.…”

Investigating the Interactive Effects of Sex Steroid Hormones and Brain-Derived Neurotrophic Factor during Adolescence on Hippocampal NMDA Receptor Expression

“…Further studies to identify whether the changes we see in GluN expression are synaptic or extrasynaptic may help to clarify this effect as previous studies suggest that the activation of synaptic GluN leads to synaptic plasticity and cell survival, while extrasynaptic activation can lead to excitotoxic cell death [ 39 ]. Indeed, a previous in vitro report showed that low concentration of estradiol (1 nM) increased the membrane expression of cortical GluN1, GluN2B, and PSD-95, while a higher concentration had no effect but reduced GluN2A [ 40 ]. Further in vivo studies assessing varying concentration of estradiol treatment would certainly be of interest here to fully elucidate the beneficial potential of estradiol on hippocampal synaptic plasticity.…”