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.
Highlights
Bar graphs represent results of quantitative real time-PCR obtained using the DDCt method for the calculation of relative quantity (RQ) of the following genes: (A) Genes involved in neuroprotection (Bcl2, brain-derived neurotrophic factor (Bdnf), and trkB); (B) Genes involved in synaptogenesis (Cdh2 and cyclin-dependent kinase 5 (Cdk5)); (C) Markers of interneurons (Gad67, Pva, neuropeptide Y (Npy)). (D) Genes involved in PV transcription (Pgc-1α and Sirt 1). (E) Gene related to local E2 biosynthesis: aromatase (Cyp19a1). ∗p < 0.05, ∗∗p < 0.001, calculated on mean Ct across biological replicates. 2008; McEwen et al, 2012), the expression of two genes involved in synaptic plasticity, namely cadherin 2 (Cdh2) (Tai et al, 2008; Bozdagi et al, 2010) and Cdk5 (Lai and Ip, 2009) was evaluated by quantitative real time PCR (qPCR)
Results showed that E2 treatment induced a significant upregulation of Cdk5 in TMT + E2 -treated rats compared with CTRL + oil- and TMT + oil-treated rats (p < 0.05); Cdh2 was significantly up-regulated in TMT + E2-treated rats compared with the CTRL + oiltreated group (p < 0.05; Figure 1B, Supplementary Table S2)
Modulation of the GABAergic system is a remarkable aspect of neuroprotective strategies, including those based on E2 administration (Iuvone et al, 1996; Dell’Anna et al, 1997; Hart et al, 2001; Czeh et al, 2005; Velísková and Velísek, 2007; Ledoux et al, 2009; Ohira et al, 2013), due to the major role exerted by interneurons in maintaining the appropriate excitatory/inhibitory synaptic balance, which is critical for hippocampal information processing (Buzsáki and Chrobak, 1995; Evstratova and Tóth, 2014)
Summary
Many findings support the modulatory role of estrogens, whose effects are mediated mainly by 17-beta estradiol (E2), on brain functions, in particular at the hippocampal level (Spencer et al, 2008), where they are responsible for the enhancement of glutamate transmission, the induction of long-term potentiation and the modulation of inhibitory activity (Brann et al, 2007; Spencer et al, 2008). E2 exerts neuroprotection through multiple mechanisms, including the enhancement of antiapoptotic and/or anti-inflammatory pathways and the modulation of neuronal plasticity (Amantea et al, 2005; Brann et al, 2007) The latter includes the E2mediated regulation of dendritic spine formation and density and/or modulation of the excitatory/inhibitory synaptic balance (Brinton, 2009). PV-expressing interneurons play a crucial role in the functional properties of the hippocampus: they participate in the synchronization of oscillations in the hippocampal network (Klausberger et al, 2005; Donato et al, 2013), and their functional/structural impairment has been associated with severe neurologic disorders, including autism (Lawrence et al, 2010; Cellot and Cherubini, 2014), schizophrenia (Cabungcal et al, 2013; Jiang et al, 2013), epilepsy (Andrioli et al, 2007), and Huntington’s disease (Cicchetti et al, 2000)
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