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4 results on '"Giulia Frumento"'

1. Changes at glutamate tripartite synapses in the prefrontal cortex of a new animal model of resilience/vulnerability to acute stress

Author

Tiziana Bonifacino, Jessica Mingardi, Roberta Facchinetti, Nathalie Sala, Giulia Frumento, Elona Ndoj, Marta Valenza, Caterina Paoli, Alessandro Ieraci, Carola Torazza, Matilde Balbi, Michele Guerinoni, Nadeem Muhammad, Isabella Russo, Marco Milanese, Caterina Scuderi, Alessandro Barbon, Luca Steardo, Giambattista Bonanno, Maurizio Popoli, and Laura Musazzi

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Stress represents a main risk factor for psychiatric disorders. Whereas it is known that even a single trauma may induce psychiatric disorders in humans, the mechanisms of vulnerability to acute stressors have been little investigated. In this study, we generated a new animal model of resilience/vulnerability to acute footshock (FS) stress in rats and analyzed early functional, molecular, and morphological determinants of stress vulnerability at tripartite glutamate synapses in the prefrontal cortex (PFC). We found that adult male rats subjected to FS can be deemed resilient (FS-R) or vulnerable (FS-V), based on their anhedonic phenotype 24 h after stress exposure, and that these two populations are phenotypically distinguishable up to two weeks afterwards. Basal presynaptic glutamate release was increased in the PFC of FS-V rats, while depolarization-evoked glutamate release and synapsin I phosphorylation at Ser9 were increased in both FS-R and FS-V. In FS-R and FS-V rats the synaptic expression of GluN2A and apical dendritic length of prelimbic PFC layers II–III pyramidal neurons were decreased, while BDNF expression was selectively reduced in FS-V. Depolarization-evoked (carrier-mediated) glutamate release from astroglia perisynaptic processes (gliosomes) was selectively increased in the PFC of FS-V rats, while GLT1 and xCt levels were higher and GS expression reduced in purified PFC gliosomes from FS-R. Overall, we show for the first time that the application of the sucrose intake test to rats exposed to acute FS led to the generation of a novel animal model of resilience/vulnerability to acute stress, which we used to identify early determinants of maladaptive response related to behavioral vulnerability to stress.

Published
2023
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2. Acute Ketamine Facilitates Fear Memory Extinction in a Rat Model of PTSD Along With Restoring Glutamatergic Alterations and Dendritic Atrophy in the Prefrontal Cortex

Author

Nathalie Sala, Caterina Paoli, Tiziana Bonifacino, Jessica Mingardi, Emanuele Schiavon, Luca La Via, Marco Milanese, Paolo Tornese, Ashok K. Datusalia, Jessica Rosa, Roberta Facchinetti, Giulia Frumento, Giulia Carini, Floramarida Salerno Scarzella, Caterina Scuderi, Lia Forti, Alessandro Barbon, Giambattista Bonanno, Maurizio Popoli, and Laura Musazzi

Subjects
acute stress, ketamine, PTSD, prefrontal cortex (PFC), glutamate transmission, dendritic arborization, Therapeutics. Pharmacology, RM1-950
Abstract

Stress represents a major risk factor for psychiatric disorders, including post-traumatic stress disorder (PTSD). Recently, we dissected the destabilizing effects of acute stress on the excitatory glutamate system in the prefrontal cortex (PFC). Here, we assessed the effects of single subanesthetic administration of ketamine (10 mg/kg) on glutamate transmission and dendritic arborization in the PFC of footshock (FS)-stressed rats, along with changes in depressive, anxious, and fear extinction behaviors. We found that ketamine, while inducing a mild increase of glutamate release in the PFC of naïve rats, blocked the acute stress-induced enhancement of glutamate release when administered 24 or 72 h before or 6 h after FS. Accordingly, the treatment with ketamine 6 h after FS also reduced the stress-dependent increase of spontaneous excitatory postsynaptic current (sEPSC) amplitude in prelimbic (PL)-PFC. At the same time, ketamine injection 6 h after FS was found to rescue apical dendritic retraction of pyramidal neurons induced by acute stress in PL-PFC and facilitated contextual fear extinction. These results show rapid effects of ketamine in animals subjected to acute FS, in line with previous studies suggesting a therapeutic action of the drug in PTSD models. Our data are consistent with a mechanism of ketamine involving re-establishment of synaptic homeostasis, through restoration of glutamate release, and structural remodeling of dendrites.

Published
2022
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3. Blocking glutamate mGlu 5 receptors with the negative allosteric modulator CTEP improves disease course in SOD1 G93A mouse model of amyotrophic lateral sclerosis

Author

Giambattista Bonanno, Nadia Bertola, Giulia Frumento, Mandeep Kumar, T P Nhung Nguyen, Tiziana Bonifacino, Arianna Roberta Zerbo, Carola Torazza, Matilde Balbi, Maurizio Viale, Aldo Profumo, Sara Ferrando, Francesca Provenzano, Marco Milanese, and Silvia Ravera

Subjects
Male, amyotrophic lateral sclerosis (ALS), Allosteric modulator, 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP), Receptor, Metabotropic Glutamate 5, SOD1, Glutamic Acid, Mice, Transgenic, Pharmacology, Mice, Superoxide Dismutase-1, medicine, Animals, ddc:610, Amyotrophic lateral sclerosis, Receptor, 2‐chloro‐4‐((2,5‐dimethyl‐1‐(4‐(trifluoromethoxy)phenyl)‐1H‐imidazol‐4‐yl)ethynyl)pyridine (CTEP), metabotropic glutamate receptor 5 (mGlu5 receptor), drug therapy [Amyotrophic Lateral Sclerosis], Superoxide Dismutase, business.industry, Amyotrophic Lateral Sclerosis, 5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP), Glutamate receptor, in vivo pharmacological treatment, Motor neuron, medicine.disease, Research Papers, genetics [Superoxide Dismutase-1], Disease Models, Animal, 2-chloro-4-((2, medicine.anatomical_structure, Spinal Cord, Metabotropic glutamate receptor, Disease Progression, Female, SOD1G93A mice, business, Research Paper, 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP), amyotrophic lateral sclerosis (ALS), in vivo pharmacological treatment, metabotropic glutamate receptor 5 (mGlu5 receptor), SOD1G93A mice, Astrocyte
Abstract

Background and Purpose The pathogenesis of amyotrophic lateral sclerosis (ALS) is not fully clarified, although excessive glutamate (Glu) transmission and the downstream cytotoxic cascades are major mechanisms for motor neuron death. Two metabotropic glutamate receptors (mGlu1 and mGlu5) are overexpressed in ALS and regulate cellular disease processes. Expression and function of mGlu5 receptors are altered at early symptomatic stages in the SOD1G93A mouse model of ALS and knockdown of mGlu5 receptors in SOD1G93A mice improved disease progression. Experimental Approach We treated male and female SOD1G93A mice with 2‐chloro‐4‐((2,5‐dimethyl‐1‐(4‐(trifluoromethoxy)phenyl)‐1H‐imidazol‐4‐yl)ethynyl)pyridine (CTEP), an orally available mGlu5 receptor negative allosteric modulator (NAM), using doses of 2 mg·kg−1 per 48 h or 4 mg·kg−1 per 24 h from Day 90, an early symptomatic disease stage. Disease progression was studied by behavioural and histological approaches. Key Results CTEP dose‐dependently ameliorated clinical features in SOD1G93A mice. The lower dose increased survival and improved motor skills in female mice, with barely positive effects in male mice. Higher doses significantly ameliorated disease symptoms and survival in both males and females, females being more responsive. CTEP also reduced motor neuron death, astrocyte and microglia activation, and abnormal glutamate release in the spinal cord, with equal effects in male and female mice. No differences were also observed in CTEP access to the brain. Conclusion and Implications Our results suggest that mGlu5 receptors are promising targets for the treatment of ALS and highlight mGlu5 receptor NAMs as effective pharmacological tools with translational potential.

Published
2021
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4. A2A-D2 Heteromers on Striatal Astrocytes: Biochemical and Biophysical Evidence

Author

Monica Averna, Giulia Frumento, Letizia Campanini, Manuela Marcoli, Simone Pelassa, Rosa Bernardi, Pietro Cortelli, Arianna Venturini, Luigi F. Agnati, Guido Maura, Chiara Cervetto, Giovanna Calandra Buonaura, Diego Guidolin, Pelassa S., Guidolin D., Venturini A., Averna M., Frumento G., Campanini L., Bernardi R., Cortelli P., Calandra Buonaura G., Maura G., Agnati L.F., Cervetto C., and Marcoli M.

Subjects
Proximity ligation assay, Striatum, Rats, Sprague-Dawley, lcsh:Chemistry, Striatal astrocyte processe, striatal slices, Receptor, lcsh:QH301-705.5, Spectroscopy, Chemistry, Communication, Glutamate receptor, General Medicine, Computer Science Applications, medicine.anatomical_structure, A2A-D2 heteromers, Striatal slice, Astrocyte, medicine.drug, Receptor, Adenosine A2A, Glutamic Acid, A2A-D2 heteromers, Co-immunoprecipitation, Proximity ligation assay, Rat striatum, Striatal astrocyte processes, Striatal slices, Catalysis, Inorganic Chemistry, Glutamatergic, Dopamine receptor D2, medicine, Animals, Physical and Theoretical Chemistry, proximity ligation assay, Molecular Biology, Animal, Receptors, Dopamine D2, rat striatum, A2A-D2 heteromer, striatal astrocyte processes, Cell Membrane, Organic Chemistry, co-immunoprecipitation, Adenosine, Corpus Striatum, Rats, lcsh:Biology (General), lcsh:QD1-999, Astrocytes, Rat, Protein Multimerization, Neuroscience
Abstract

Our previous findings indicate that A2A and D2 receptors are co-expressed on adult rat striatal astrocytes and on the astrocyte processes, and that A2A-D2 receptor−receptor interaction can control the release of glutamate from the processes. Functional evidence suggests that the receptor−receptor interaction was based on heteromerization of native A2A and D2 receptors at the plasma membrane of striatal astrocyte processes. We here provide biochemical and biophysical evidence confirming that receptor−receptor interaction between A2A and D2 receptors at the astrocyte plasma membrane is based on A2A-D2 heteromerization. To our knowledge, this is the first direct demonstration of the ability of native A2A and D2 receptors to heteromerize on glial cells. As striatal astrocytes are recognized to be involved in Parkinson’s pathophysiology, the findings that adenosine A2A and dopamine D2 receptors can form A2A-D2 heteromers on the astrocytes in the striatum (and that these heteromers can play roles in the control of the striatal glutamatergic transmission) may shed light on the molecular mechanisms involved in the pathogenesis of the disease.

Published
2019

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