Alessandra Tempio

Ciclo: XXXIV

Data inizio: 01/01/2019

Curriculum: Biomediche e Precliniche

Borsa: MIUR PON R&I

Titolo tesi: Role of 5-HT7 receptors for serotonin in mitochondrial activity and in the pathophysiology of Fragile X Syndrome

Abstract: Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism. Fmr1 knockout (Fmr1 KO) mice, a murine model of FXS, exhibit impairment in mitochondrial activity and in synaptic plasticity, with an exaggerated long‐term depression induced by activation of metabotropic glutamate receptors (mGluR‐LTD). Our research group has previously demonstrated that activation of serotonin 5-HT7 receptors reverses the mGluR-LTD in the hippocampus of wild-type (WT) and Fmr1 KO mice. Here I highlighted some molecular mechanism involved in 5-HT7 -mediated reversal of mGluR‐LTD in the synapse between CA3 and CA1 pyramidal neurons using the patch clamp technique on hippocampal slices from wild-type and Fmr1 KO mice. My data indicate that the blockade of cyclin‐dependent kinase 5 (Cdk5) enhanced mGluR‐LTD in WT hippocampal neurons to the level observed in Fmr1 KO neurons and abolished the 5-HT7 -mediated reversal of mGluR‐LTD both in WT and Fmr1 KO neurons, showing that Cdk5 is involved in 5-HT7 –mediated reversal effect. In addition, my data indicate that Akt inhibition abolished the mGluR-LTD in WT, but not in Fmr1 KO mice, pointing out that Akt is essential for mGluR-LTD only in WT slices. Moreover, in presence of an inhibitor of Akt, the effect induced by the activation of 5-HT7 receptor on mGluR-LTD was not abolished; thereby 5- HT7 -mediated reversal of mGluR‐LTD does not require Akt activation. Then, I evaluated the role of protein synthesis on mGluR-LTD. When the inhibitor of mRNA translation anisomycin was present in the intracellular solution, mGluR‐LTD was abolished in WT but not in Fmr1 KO neurons, indicating that protein translation is necessary for mGluR-LTD only in WT neurons. Additionally, my data show that 5-HT7 -mediated effect on mGluR-LTD was abolished in the presence of anisomycin, thus required protein translation. Lastly, I demonstrated for the first time that 5-HT7 receptors are present in mitochondria of a neuroblastoma cell line and the application of a 5-HT7 inverse agonist weakly influenced the mitochondrial cytochrome c oxidase.

Tutor: Ciranna

Data Conseguimento Titolo: 21/07/2021

Linkedin: Indicate il link

Email: alessandra.tempio@gmail.com

Periodi all'estero- Sede e data: Ipmc - Institute Pharmacology Moléculaire Et Cellulaire - 660 Rte des Lucioles, 06560 Valbonne France -  From 1/05/2021 to 31-10-2021

Esperienze post-Dottorato ed attuale occupazione: Research FRAXA Fellow (dal 01/10/2022) - Ipmc - Institute Pharmacology Moléculaire Et Cellulaire - 660 Rte des Lucioles, 06560 Valbonne France