Estrogen Receptors and Type 1 Metabotropic Glutamate Receptors Are Interdependent in Protecting Cortical Neurons against β-Amyloid Toxicity

Spampinato, Simona Federica; Molinaro, Gemma; Merlo, Sara; Iacovelli, Luisa; Caraci, Filippo; Battaglia, Giuseppe; Nicoletti, Ferdinando; Bruno, Valeria; Sortino, Maria Angela

doi:10.1124/mol.111.074021

Cited by 32 publications

(17 citation statements)

References 60 publications

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“…However, there is evidence that ERα may be more important in biological functions associated with autism, including early cortical development processes [64], regulation of transcriptional targets in the cortex [64,65], neuroprotection against cytotoxicity [66] and ischemia [67], and social discrimination [68]. Nevertheless, the mechanisms through which ERβ may be involved in regulation of RORA deserve further study since ERβ is also known to be highly expressed in cortex, amygdala, and cerebellum, where AR is also highly expressed [69].…”

Section: Discussionmentioning

confidence: 99%

Differential recruitment of coregulators to the RORA promoter adds another layer of complexity to gene (dys) regulation by sex hormones in autism

Sarachana

2013

Mol Autism

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BackgroundOur independent cohort studies have consistently shown the reduction of the nuclear receptor RORA (retinoic acid-related orphan receptor-alpha) in lymphoblasts as well as in brain tissues from individuals with autism spectrum disorder (ASD). Moreover, we have found that RORA regulates the gene for aromatase, which converts androgen to estrogen, and that male and female hormones regulate RORA in opposite directions, with androgen suppressing RORA, suggesting that the sexually dimorphic regulation of RORA may contribute to the male bias in ASD. However, the molecular mechanisms through which androgen and estrogen differentially regulate RORA are still unknown.MethodsHere we use functional knockdown of hormone receptors and coregulators with small interfering RNA (siRNA) to investigate their involvement in sex hormone regulation of RORA in human neuronal cells. Luciferase assays using a vector containing various RORA promoter constructs were first performed to identify the promoter regions required for inverse regulation of RORA by male and female hormones. Sequential chromatin immunoprecipitation methods followed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analyses of RORA expression in hormone-treated SH-SY5Y cells were then utilized to identify coregulators that associate with hormone receptors on the RORA promoter. siRNA-mediated knockdown of interacting coregulators was performed followed by qRT-PCR analyses to confirm the functional requirement of each coregulator in hormone-regulated RORA expression.ResultsOur studies demonstrate the direct involvement of androgen receptor (AR) and estrogen receptor (ER) in the regulation of RORA by male and female hormones, respectively, and that the promoter region between −10055 bp and −2344 bp from the transcription start site of RORA is required for the inverse hormonal regulation. We further show that AR interacts with SUMO1, a reported suppressor of AR transcriptional activity, whereas ERα interacts with the coactivator NCOA5 on the RORA promoter. siRNA-mediated knockdown of SUMO1 and NCOA5 attenuate the sex hormone effects on RORA expression.ConclusionsAR and SUMO1 are involved in the suppression RORA expression by androgen, while ERα and NCOA5 collaborate in the up-regulation of RORA by estrogen. While this study offers a better understanding of molecular mechanisms involved in sex hormone regulation of RORA, it also reveals another layer of complexity with regard to gene regulation in ASD. Inasmuch as coregulators are capable of interacting with a multitude of transcription factors, aberrant expression of coregulator proteins, as we have seen previously in lymphoblasts from individuals with ASD, may contribute to the polygenic nature of gene dysregulation in ASD.

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Section: Discussionmentioning

confidence: 99%

Differential recruitment of coregulators to the RORA promoter adds another layer of complexity to gene (dys) regulation by sex hormones in autism

Sarachana

2013

Mol Autism

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“…This is particularly relevant in studies dedicated to the pharmacological characterization of presynaptic mGlu1 autoreceptors modulating glutamate release from nerve endings. Actually, although the existence of mGlu1 receptors in astrocytes is matter of discussion (Spampinato et al, 2012 and references therein), the possibility that these receptors are expressed in gliosomes (i.e., particles originating from astrocyte arborisations during tissue homogenisation to isolate synaptosomes, Milanese et al, 2009) deserves attention. If present, glial mGlu1 receptors could elicit glutamate release, then indirectly altering the efficiency of glutamate exocytosis from the synaptosomal suspension.…”

Section: The Up–down Superfusion Of a Thin Layer Of Synaptosomes: Sommentioning

confidence: 99%

Presynaptic Release-Regulating mGlu1 Receptors in Central Nervous System

Pittaluga

2016

Front. Pharmacol.

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Group I metabotropic glutamate (mGlu) receptors consists of mGlu1 and mGlu5 receptor subtypes. These receptors are widely distributed in the central nervous system (CNS), where they preferentially mediate facilitatory signaling in neurones and glial cells, mainly by favoring phospholipase (PLC) translocation. Based on the literature so far available, group I Metabotropic glutamate receptors (mGluRs) are preferentially expressed at the postsynaptic side of chemical synapsis, where they participate in the progression of the chemical stimulus. Studies, however, have shown the presence of these receptors also at the presynaptic level, where they exert several functions, including the modulation of transmitter exocytosis. Presynaptic Group I mGluRs can be both autoreceptors regulating release of glutamate and heteroreceptors regulating the release of various transmitters, including GABA, dopamine, noradrenaline, and acetylcholine. While the existence of presynaptic release-regulating mGlu5 receptors is largely recognized, the possibility that mGlu1 receptors also are present at this level has been a matter of discussion for a long time. A large body of evidence published in the last decade, however, supports this notion. This review aims at revisiting the data from in vitro studies concerning the existence and the role of release-regulating mGlu1 receptors presynaptically located in nerve terminals isolated from selected regions of the CNS. The functional interaction linking mGlu5 and mGlu1 receptor subtypes at nerve terminals and their relative contributions as modulators of central transmission will also be discussed. We apologize in advance for omission in our coverage of the existing literature.

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“…All animal experimental procedures were carried out in accordance with the directives of the Italian and EU regulations for care and use of experimental animals (DL116/92) and approved by the Italian Ministry of Health. Preparation of glial cell cultures was carried out as previously described (Spampinato et al, 2012 ) using 1- to 3-day-old Sprague-Dawley rats (Harlan, Udine, Italy). After removal of meninges and isolation of cortices, cells were dispersed by mechanical and enzymatic dissociation using a solution of trypsin diluted in Hank’s Balanced Salt Solution.…”

Section: Methodsmentioning

confidence: 99%

Glial metabotropic glutamate receptor-4 increases maturation and survival of oligodendrocytes

Spampinato

Merlo

Chisari

et al. 2015

Front. Cell. Neurosci.

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Group III metabotropic glutamate (mGlu) receptors mediate important neuroprotective and anti-inflammatory effects. Stimulation of mGlu4 receptor reduces neuroinflammation in a mouse model of experimental autoimmune encephalomyelitis (EAE) whereas mGlu4 knockout mice display exacerbated EAE clinical scores. We now show that mGlu4 receptors are expressed in oligodendrocytes, astrocytes and microglia in culture. Oligodendrocytes express mGlu4 receptors only at early stages of maturation (O4 positive), but not when more differentiated (myelin basic protein, MBP positive). Treatment of immature oligodendrocytes with the mGlu4 receptor agonist L-2-Amino-4-phosphonobutyrate (L-AP4; 50 μM for 48 h) accelerates differentiation with enhanced branching and earlier appearance of MBP staining. Oligodendrocyte death induced by exposure to 1 mM kainic acid for 24 h is significantly reduced by a 30-min pretreatment with L-AP4 (50 μM), an effect observed only in the presence of astrocytes, mimicked by the specific mGlu4 receptor positive allosteric modulator N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) (30 μM) and prevented by pretreatment with the mGlu4 receptor antagonist, cyclopropyl-4-phosphonophenylglycine (CPPG) (100 μM). In astrocytes, mGlu4 receptor is the most expressed among group III mGlu receptors, as by Quantitative real time PCR (QRT-PCR), and its silencing prevents protective effects. Protection is also observed when conditioned medium (CM) from L-AP4-pretreated astrocytes is transferred to oligodendrocytes challenged with kainic acid. Transforming growth factor β (TGF-β) mediates the increased oligodendrocyte survival as the effect of L-AP4 is mimicked by addition of 10 ng/ml TGF-β and prevented by incubation with a neutralizing anti-TGF-β antibody. In contrast, despite the expression of mGlu4 receptor in resting and activated microglia, CM from L-AP4-stimulated microglia does not modify kainate-induced oligodendrocyte toxicity. Our results suggest that mGlu4 receptors expressed in astrocytes mediate enhanced survival of oligodendrocytes under conditions of excitotoxicity.

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Estrogen Receptors and Type 1 Metabotropic Glutamate Receptors Are Interdependent in Protecting Cortical Neurons against β-Amyloid Toxicity

Cited by 32 publications

References 60 publications

Differential recruitment of coregulators to the RORA promoter adds another layer of complexity to gene (dys) regulation by sex hormones in autism

Differential recruitment of coregulators to the RORA promoter adds another layer of complexity to gene (dys) regulation by sex hormones in autism

Presynaptic Release-Regulating mGlu1 Receptors in Central Nervous System

Glial metabotropic glutamate receptor-4 increases maturation and survival of oligodendrocytes

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