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  • Molinaro, Gemma  (35)
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  • 1
    Language: English
    In: Endocrinology, December 2012, Vol.153(12), pp.5940-8
    Description: Pretreatment with 10 nm 17β-estradiol (17βE2) or 100 μm of the metabotropic glutamate 1 receptor (mGlu1R) agonist, dihydroxyphenylglycine (DHPG), protected neurons against N-methyl-d-aspartate (NMDA) toxicity. This effect was sensitive to blockade of both estrogen receptors and mGlu1R by their respective antagonists. In contrast, 17βE2 and/or DHPG, added after a low-concentration NMDA pulse (45 μm), produced an opposite effect, i.e. an exacerbation of NMDA toxicity. Again this effect was prevented by both receptor antagonists. In support of an interaction of estrogen receptors and mGlu1R in mediating a neurotoxic response, exacerbation of NMDA toxicity by 17βE2 disappeared when cultures were treated with DHPG prior to NMDA challenge, and conversely, potentiation of NMDA-induced cell death by DHPG was prevented by pretreatment with 17βE2. Addition of calpain III inhibitor (10 μm), 2 h before NMDA, prevented the increased damage induced by the two agonists, an affect that can be secondary to cleavage of mGlu1R by calpain. Accordingly, NMDA stimulation reduced expression of the full-length (140 kDa) mGluR1, an effect partially reversed by calpain inhibitor. Finally, in the presence of NMDA, the ability of 17βE2 to stimulate phosphorylation of AKT and ERK was impaired. Pretreatment with calpain inhibitor prevented the reduction of phosphorylated ERK but had no significant effect on phosphorylated AKT. Accordingly, the inhibition of ERK signaling by U0126 (1 μm) counteracted the effect of calpain inhibition on 17βE2-induced exacerbation of NMDA toxicity. The present data confirm the dual role of estrogens in neurotoxicity/neuroprotection and highlight the role of the timing of exposure to estrogens.
    Keywords: Cell Death -- Drug Effects ; Estradiol -- Metabolism ; N-Methylaspartate -- Pharmacology ; Neurons -- Metabolism ; Receptors, Metabotropic Glutamate -- Metabolism
    ISSN: 00137227
    E-ISSN: 1945-7170
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  • 2
    In: PLoS ONE, 2012, Vol.7(9)
    Description: We examined the role of endogenous dopamine (DA) in regulating the number of intrinsic tyrosine hydroxylase-positive (TH + ) striatal neurons using mice at postnatal day (PND) 4 to 8, a period that corresponds to the developmental peak in the number of these neurons. We adopted the strategy of depleting endogenous DA by a 2-day treatment with α-methyl- p -tyrosine (αMpT, 150 mg/kg, i.p.). This treatment markedly increased the number of striatal TH + neurons, assessed by stereological counting, and the increase was highly correlated to the extent of DA loss. Interestingly, TH + neurons were found closer to the clusters of DA fibers after DA depletion, indicating that the concentration gradient of extracellular DA critically regulates the distribution of striatal TH + neurons. A single i.p. injection of the D1 receptor antagonist, SCH23390 (0.1 mg/kg), the D2/D3 receptor antagonist, raclopride (0.1 mg/kg), or the D4 receptor antagonist, L-745,870 (5 mg/kg) in mice at PND4 also increased the number of TH + neurons after 4 days. Treatment with the D1-like receptor agonist SKF38393 (10 mg/kg) or with the D2-like receptor agonist, quinpirole (1 mg/kg) did not change the number of TH + neurons. At least the effects of SCH23390 were prevented by a combined treatment with SKF38393. Immunohistochemical analysis indicated that striatal TH + neurons expressed D2 and D4 receptors, but not D1 receptors. Moreover, treatment with the α4β2 receptor antagonist dihydro-β-erythroidine (DHβE) (3.2 mg/kg) also increased the number of TH + neurons. The evidence that DHβE mimicked the action of SCH23390 in increasing the number of TH + neurons supports the hypothesis that activation of D1 receptors controls the number of striatal TH + neurons by enhancing the release of acetylcholine. These data demonstrate for the first time that endogenous DA negatively regulates the number of striatal TH + neurons by direct and indirect mechanisms mediated by multiple DA receptor subtypes.
    Keywords: Research Article ; Biology
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: 2012, Vol.7(9), p.e44025
    Description: We examined the role of endogenous dopamine (DA) in regulating the number of intrinsic tyrosine hydroxylase-positive (TH + ) striatal neurons using mice at postnatal day (PND) 4 to 8, a period that corresponds to the developmental peak in the number of these neurons. We adopted the strategy of depleting endogenous DA by a 2-day treatment with α-methyl- p -tyrosine (αMpT, 150 mg/kg, i.p.). This treatment markedly increased the number of striatal TH + neurons, assessed by stereological counting, and the increase was highly correlated to the extent of DA loss. Interestingly, TH + neurons were found closer to the clusters of DA fibers after DA depletion, indicating that the concentration gradient of extracellular DA critically regulates the distribution of striatal TH + neurons. A single i.p. injection of the D1 receptor antagonist, SCH23390 (0.1 mg/kg), the D2/D3 receptor antagonist, raclopride (0.1 mg/kg), or the D4 receptor antagonist, L-745,870 (5 mg/kg) in mice at PND4 also increased the number of TH + neurons after 4 days. Treatment with the D1-like receptor agonist SKF38393 (10 mg/kg) or with the D2-like receptor agonist, quinpirole (1 mg/kg) did not change the number of TH + neurons. At least the effects of SCH23390 were prevented by a combined treatment with SKF38393. Immunohistochemical analysis indicated that striatal TH + neurons expressed D2 and D4 receptors, but not D1 receptors. Moreover, treatment with the α4β2 receptor antagonist dihydro-β-erythroidine (DHβE) (3.2 mg/kg) also increased the number of TH + neurons. The evidence that DHβE mimicked the action of SCH23390 in increasing the number of TH + neurons supports the hypothesis that activation of D1 receptors controls the number of striatal TH + neurons by enhancing the release of acetylcholine. These data demonstrate for the first time that endogenous DA negatively regulates the number of striatal TH + neurons by direct and indirect mechanisms mediated by multiple DA receptor subtypes.
    Keywords: Research Article ; Biology ; Neuroscience ; Developmental Biology
    E-ISSN: 1932-6203
    Source: PLoS
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  • 4
    Language: English
    In: Neuron, 02 October 2013, Vol.80(1), pp.72-79
    Description: A novel experience induces the gene as well as plasticity of CA1 neural networks. To understand how these are linked, we briefly exposed GFP reporter mice of transcription to a novel environment. Excitatory synaptic function of CA1 neurons with recent in vivo induction ( GFP+) was similar to neighboring noninduced neurons. However, in response to group 1 metabotropic glutamate receptor (mGluR) activation, GFP+ neurons preferentially displayed long-term synaptic depression (mGluR-LTD) and robust increases in dendritic Arc protein. mGluR-LTD in GFP+ neurons required rapid protein synthesis and , suggesting that dendritic translation of Arc underlies the priming of mGluR-LTD. In support of this idea, novelty exposure increased messenger RNA in CA1 dendrites and promoted mGluR-induced translation of Arc in hippocampal synaptoneurosomes. Repeated experience suppressed synaptic transmission onto GFP+ neurons and occluded mGluR-LTD ex vivo. mGluR-LTD priming in neurons with similar activation history may contribute to encoding a novel environment. The consequence of experience-induced Arc gene on synaptic function is unknown. Jakkamsetti et al. find that novelty-induced Arc primes CA1 neurons for mGluR-dependent long-term synaptic depression through rapid translation of dendritic Arc mRNA, which may contribute to encoding of a salient experience.
    Keywords: Biology ; Anatomy & Physiology
    ISSN: 0896-6273
    E-ISSN: 1097-4199
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  • 5
    Language: English
    In: Neuroscience Letters, 2010, Vol.478(3), pp.128-130
    Description: The -amino acid, -aspartate, is abundant in the developing brain, yet its function is unknown. Addition of -aspartate to hippocampal or cortical slices prepared from 8- to 9-day-old rats stimulated polyphosphoinositide (PI) hydrolysis to a slightly greater extent than -glutamate. The action of -aspartate was concentration-dependent with an apparent EC value of 1 mM and a maximal stimulation of 6- and 20-fold in cortical and hippocampal slices, respectively. Stimulation of PI hydrolysis by -aspartate was largely reduced by pharmacological blockade of mGlu5 metabotropic glutamate receptors with 2-methyl-6-(phenylethynyl)pyridine. These findings suggest that -aspartate behaves as an endogenous agonist of mGlu5 receptors during early postnatal life.
    Keywords: D-Aspartate ; Metabotropic Glutamate Receptors ; Polyphosphoinositide Hydrolysis ; Hippocampal Slices ; Cortical Slices ; Medicine ; Anatomy & Physiology
    ISSN: 0304-3940
    E-ISSN: 1872-7972
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  • 6
    Language: English
    In: PLoS ONE, 01 January 2011, Vol.6(1), p.e16447
    Description: The identification of mechanisms that mediate stress-induced hippocampal damage may shed new light into the pathophysiology of depressive disorders and provide new targets for therapeutic intervention. We focused on the secreted glycoprotein Dickkopf-1 (Dkk-1), an inhibitor of the canonical Wnt pathway, involved in neurodegeneration. Mice exposed to mild restraint stress showed increased hippocampal levels of Dkk-1 and reduced expression of β-catenin, an intracellular protein positively regulated by the canonical Wnt signalling pathway. In adrenalectomized mice, Dkk-1 was induced by corticosterone injection, but not by exposure to stress. Corticosterone also induced Dkk-1 in mouse organotypic hippocampal cultures and primary cultures of hippocampal neurons and, at least in the latter model, the action of corticosterone was reversed by the type-2 glucocorticoid receptor antagonist mifepristone. To examine whether induction of Dkk-1 was causally related to stress-induced hippocampal damage, we used doubleridge mice, which are characterized by a defective induction of Dkk-1. As compared to control mice, doubleridge mice showed a paradoxical increase in basal hippocampal Dkk-1 levels, but no Dkk-1 induction in response to stress. In contrast, stress reduced Dkk-1 levels in doubleridge mice. In control mice, chronic stress induced a reduction in hippocampal volume associated with neuronal loss and dendritic atrophy in the CA1 region, and a reduced neurogenesis in the dentate gyrus. Doubleridge mice were resistant to the detrimental effect of chronic stress and, instead, responded to stress with increases in dendritic arborisation and neurogenesis. Thus, the outcome of chronic stress was tightly related to changes in Dkk-1 expression in the hippocampus. These data indicate that induction of Dkk-1 is causally related to stress-induced hippocampal damage and provide the first evidence that Dkk-1 expression is regulated by corticosteroids in the central nervous system. Drugs that rescue the canonical Wnt pathway may attenuate hippocampal damage in major depression and other stress-related disorders.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: Journal of medicinal chemistry, 28 April 2011, Vol.54(8), pp.3086-90
    Description: We report benzo[b]thiophene derivatives synthesized according to a dual strategy. 8j, 9c, and 9e with affinity values toward 5-HT(7)R and 5-HTT were selected to probe their antidepressant activity in vivo using the forced swimming text (FST). The results showed significant antidepressant activity after chronic treatment. 9c was effective in reducing the immobility time in FST even after acute treatment. These findings identify these compounds as a new class of antidepressants with a rapid onset of action.
    Keywords: Antidepressive Agents -- Therapeutic Use ; Thiophenes -- Therapeutic Use
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 8
    Language: English
    In: Current Pharmaceutical Design, 2013, Vol.19(36), p.6480-6490
    Description: The term "Autism Spectrum" is often used to describe disorders that are currently classified as Pervasive Developmental Disorders. These disorders are typically characterized by social deficits, communication difficulties, stereotyped or repetitive behaviors and/or cognitive delays or mental retardation; sometimes they present high comorbidity rates with epilepsy. Although these diagnoses share some common features, individuals with these disorders are thought to be "on the spectrum" because of differences in severity across these domains. Recent advances in the genetics of autism spectrum disorders (ASDs) are offering new valuable insights into molecular and cellular mechanisms of pathology. Of particular interest are transgenic technologies that allowed the engineering of several mouse models mimicking different kinds of monogenic heritable forms of ASDs. These transgenic models provide excellent opportunities to explore in detail cellular and molecular mechanisms underlying disease pathology and to identify novel targets for therapeutic intervention. Increasing evidence suggests that the pathophysiological core of the murine model is primarily due to changes in normal synaptic transmission and plasticity. Here, we will extensively review the synaptic alterations across different animal models of ASDs and recapitulate the pharmacological strategies aimed at rescuing hippocampal plasticity phenotypes. We describe how pharmacological modulation of mGlu5 receptor, through the use of positive or negative allosteric modulators (depending on the specific disorder), may represent a promising therapeutic strategy for ASDs treatment.
    Keywords: Synaptic Plasticity Long-Term Potentiation Long-Term Depression Monogenic Autism Mglurs.
    ISSN: 1381-6128
    E-ISSN: 1873-4286
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  • 9
    Language: English
    In: Neuropharmacology, March 2013, Vol.66, pp.143-150
    Description: Synaptic transmission is essential for early development of the central nervous system. However, the mechanisms that regulate early synaptic transmission in the cerebral cortex are unclear. PKMζ is a kinase essential for the maintenance of LTP. We show for the first time that inhibition of PKMζ produces a profound depression of basal synaptic transmission in neonatal, but not adult, rat perirhinal cortex. This suggests that synapses in early development are in a constitutive LTP-like state. Furthermore, basal synaptic transmission in immature, but not mature, perirhinal cortex relies on persistent activity of metabotropic glutamate (mGlu) receptor, PI3Kinase and mammalian target of rapamycin (mTOR). Thus early in development, cortical synapses exist in an LTP-like state maintained by tonically active mGlu receptor-, mTOR- and PKMζ- dependent cascades. These results provide new understanding of the molecular mechanisms that control synapses during development and may aid our understanding of developmental disorders such as autism and schizophrenia. This article is part of a Special Issue entitled ‘Metabotropic Glutamate Receptors’. ► Synapses are in a constitutive LTP-like state in the developing perirhinal cortex. ► PKMζ inhibition reduces synaptic transmission in the developing perirhinal cortex. ► Group-I mGlu receptors support the LTP-like state in the perirhinal cortex. ► PKMζ, PI3Kinase and mTOR are down stream of group-I mGlu receptors.
    Keywords: Ltp ; Pkmζ ; Group I Mglu Receptor ; Cerebral Cortex ; Development ; Mtor ; Protein Translation ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0028-3908
    E-ISSN: 1873-7064
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  • 10
    Language: English
    In: Neuropharmacology, August 2015, Vol.95, pp.50-58
    Description: Neuroadaptive changes involving the indirect pathway of the basal ganglia motor circuit occur in the early phases of parkinsonism. The precise identification of these changes may shed new light into the pathophysiology of parkinsonism and better define the time window of pharmacological intervention. We examined some of these changes in mice challenged with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), or with the dopamine receptor blocker, haloperidol. These two models clearly diverge from Parkinson's disease (PD); however, they allow an accurate time-dependent analysis of neuroadaptive changes occurring in the striatum. Acute haloperidol injection caused a significant increase in the transcripts of mGlu4 receptors, CB1 receptors and preproenkephalin-A at 2 and 24 h, and a reduction in the transcripts of mGlu5 and A receptors at 2 h. At least changes in the expression of mGlu4 receptors might be interpreted as compensatory because haloperidol-induced catalepsy was enhanced in mGlu4 mice. Mice injected with 30 mg/kg of MPTP also showed an increase in the transcripts of mGlu4 receptors, CB1 receptors, and preproenkephalin-A at 3 d, and a reduction of the transcript of A receptors at 1 d in the striatum. Genetic deletion of mGlu4 receptors altered the functional response to MPTP, assessed by counting c-Fos neurons in the external globus pallidus and ventromedial thalamic nucleus. These findings offer the first evidence that changes in the expression of mGlu4 and mGlu5 receptors occur in acute models of parkinsonisms, and lay the groundwork for the study of these changes in models that better recapitulate the temporal profile of nigrostriatal dysfunction associated with PD.
    Keywords: Metabotropic Glutamate Receptors ; Haloperidol ; Mptp ; Parkinsonism ; Indirect Pathway ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0028-3908
    E-ISSN: 1873-7064
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