Estrogen administration modulates hippocampal GABAergic subpopulations in the hippocampus of trimethyltin-treated rats

Abstract

Given the well-documented involvement of estrogens in the modulation of hippocampal functions in both physiological and pathological conditions, the present study investigates the effects of 17-beta estradiol (E2) administration in the rat model of hippocampal neurodegeneration induced by trimethyltin (TMT) administration (8 mg/kg), characterized by loss of pyramidal neurons in CA1, CA3/hilus hippocampal subfields, associated with astroglial and microglial activation, seizures and cognitive impairment. After TMT/saline treatment, ovariectomized animals received two doses of E2 (0.2 mg/kg intra-peritoneal) or vehicle, and were sacrificed 48 h or 7 days after TMT-treatment. Our results indicate that in TMT-treated animals E2 administration induces the early (48 h) upregulation of genes involved in neuroprotection and synaptogenesis, namely Bcl2, trkB, cadherin 2 and cyclin-dependent-kinase-5. Increased expression levels of glutamic acid decarboxylase (gad) 67, neuropeptide Y (Npy), parvalbumin, Pgc-1α and Sirtuin 1 genes, the latter involved in parvalbumin (PV) synthesis, were also evident. Unbiased stereology performed on rats sacrificed 7 days after TMT treatment showed that although E2 does not significantly influence the extent of TMT-induced neuronal death, significantly enhances the TMT-induced modulation of GABAergic interneuron population size in selected hippocampal subfields. In particular, E2 administration causes, in TMT-treated rats, a significant increase in the number of GAD67-expressing interneurons in CA1 stratum oriens, CA3 pyramidal layer, hilus and dentate gyrus, accompanied by a parallel increase in NPY-expressing cells, essentially in the same regions, and of PV-positive cells in CA1 pyramidal layer. The present results add information concerning the role of in vivo E2 administration on mechanisms involved in cellular plasticity in the adult brain.

The Neuroprotective Effects of 17β-Estradiol Pretreatment in a Model of Neonatal Hippocampal Injury Induced by Trimethyltin

“…or vehicle (sesame oil). The dose of E2 was chosen in accordance with beneficial effects described in our previous study in TMT-treated adult rats ( Corvino et al, 2015 ) and with previously reported early treatment with E2 associated with neuroprotective effects in neonatal rats ( Pansiot et al, 2016 ). The same E2/vehicle dose was administered on post-treatment day 1 (P6).…”

“…E2 is not only able to counteract neuronal death, but also exerts neuroprotection by enhancing neural plasticity, particularly at the hippocampal level ( Brinton, 2009 ). Numerous studies provide evidence that E2 exerts neuroprotective effects by inducing phenotypic changes in the size of different GABAergic subpopulations, in particular enhancing neuropeptide Y (NPY) expression ( Nakamura and McEwen, 2005 ; Corvino et al, 2015 ) and modulating the size of PV-positive interneuron subpopulation ( Rewal et al, 2005 ; Macrì et al, 2010 ). Because of the relevance of hippocampal dysfunction and interneuron imbalance in neurodevelopmental and neuropsychiatric diseases, in the present study we investigated the effects of pretreatment with E2 on different aspects related to TMT-induced hippocampal injury in neonatal rats, including neuronal death, neuroinflammation and interneuron impairment, with the aim of providing an exhaustive description of cellular and molecular events related to possible neuroprotective approaches in early hippocampal damage.…”

Presynaptic inhibition decreases when estrogen level rises

“…The decrease in GAD results in a suppression of the conversion of glutamate to GABA and therefore effectively down regulates GABA. 30 We acknowledge this mechanism of GABA regulation has not been confirmed in the spinal cord, but maintain its plausibility as it is present in both the hippocampus 26 and striatum. 17 Furthermore, it is well established that in patients with conditions such as spinal cord injury and other spasticity related conditions, PI is diminished and represents a decrease in control and modulatory capability of the system.…”

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

“…The role of estradiol in the regulation of reactive synaptogenesis under neurodegenerative conditions has also been analyzed in other neuropathological models. In a model of hippocampal neurodegeneration in ovariectomized female rats, induced by the intraperitoneal administration of the neurotoxic trimethylin, the neuroprotective actions of estradiol were associated with the upregulation of the expression of genes involved in synaptogenesis, such as Bcl2, trkB, cadherin 2 and cyclin-dependent-kinase-5 (Corvino et al, 2015; Table 2). However, synaptogenesis was not directly assessed in this study and the upregulated genes also participate in other cellular functions, including the regulation of apoptosis.…”

“…In the kainic acid rat model of excitotoxic injury, the hormone promotes the survival of somatostatin and neuropetide Y immunoreactive hilar interneurons in ovariectomized rats (Azcoitia et al, 1998;Velísková, 2006;Table 2). In another hippocampal model of neurodegeneration, the administration of trimethylin to ovariectomized rats, estradiol increases the expression of the interneuronal markers glutamic acid decarboxylase 67, neuropeptide Y and parvalbumin (Corvino et al, 2015;Table 2). Estradiol also prevents the reduction in parvalbumin expression in ovariectomized rats submitted to MCAO ischemic brain injury and in hippocampal neuronal cultures exposed to glutamate (Koh, 2014).…”