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      Activation of Serotonin 5-HT 7 Receptors Modulates Hippocampal Synaptic Plasticity by Stimulation of Adenylate Cyclases and Rescues Learning and Behavior in a Mouse Model of Fragile X Syndrome

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          Abstract

          We have previously demonstrated that activation of serotonin 5-HT 7 receptors (5-HT 7R) reverses metabotropic glutamate receptor-mediated long term depression (mGluR-LTD) in the hippocampus of wild-type (WT) and Fmr1 Knockout (KO) mice, a model of Fragile X Syndrome (FXS) in which mGluR-LTD is abnormally enhanced. Here, we have investigated intracellular mechanisms underlying the effect of 5-HT 7R activation using patch clamp on hippocampal slices. Furthermore, we have tested whether in vivo administration of LP-211, a selective 5-HT 7R agonist, can rescue learning and behavior in Fmr1 KO mice. In the presence of an adenylate cyclase blocker, mGluR-LTD was slightly enhanced in WT and therefore the difference between mGluR-LTD in WT and Fmr1 KO slices was no longer present. Conversely, activation of adenylate cyclase by either forskolin or Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) completely reversed mGluR-LTD in WT and Fmr1 KO. 5-HT 7R activation reversed mGluR-LTD in WT and corrected exaggerated mGluR-LTD in Fmr1 KO; this effect was abolished by blockade of either adenylate cyclase or protein kinase A (PKA). Exposure of hippocampal slices to LP-211 caused an increased phosphorylation of extracellular signal regulated kinase (ERK), an intracellular effector involved in mGluR-LTD, in WT mice. Conversely, this effect was barely detectable in Fmr1 KO mice, suggesting that 5-HT 7R-mediated reversal of mGluR-LTD does not require ERK stimulation. Finally, an acute in vivo administration of LP-211 improved novel object recognition (NOR) performance in WT and Fmr1 KO mice and reduced stereotyped behavior in Fmr1 KO mice. Our results indicate that mGluR-LTD in WT and Fmr1 KO slices is bidirectionally modulated in conditions of either reduced or enhanced cAMP formation. Activation of 5-HT 7 receptors reverses mGluR-LTD by activation of the cAMP/PKA intracellular pathway. Importantly, a systemic administration of a 5-HT 7R agonist to Fmr1 KO mice corrected learning deficits and repetitive behavior. We suggest that selective 5-HT 7R agonists might become novel pharmacological tools for FXS therapy.

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          Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety.

          An increasing number of investigators utilize the marble-burying assay despite the paucity of information available regarding what underlies the behavior. We tested the possibility that a genetic component underlies marble burying in mice and if there is a genetic correlation with other anxiety-like traits. Since findings reported in the literature indicate that marble-burying behavior reflects an anxiety-like response, we explored the assumption that the novel nature of a marble induces this anxiety. Finally, we investigated how the natural response of a mouse to dig relates to the marble-burying phenomenon. We examined ten different inbred mouse strains to determine if marble-burying behavior is genetically regulated and correlated with anxiety-like traits in two other assays. We employed multiple variants of the "traditional" marble-burying assay to address how issues such as the novelty of marbles and digging behavior contribute to marble burying. Marble-burying behavior varied across strain and did not correlate with anxiety measures in other assays. Multiple tests conducted to reduce the novelty of marbles failed to alter burying behavior. Additionally, digging behavior correlated with marble burying, and the presence of marbles did not significantly impact the digging response. Our results indicate that mouse marble burying is genetically regulated, not correlated with other anxiety-like traits, not stimulated by novelty, and is a repetitive behavior that persists/perseveres with little change across multiple exposures. Marble burying is related to digging behavior and may in fact be more appropriately considered as an indicative measure of repetitive digging.
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            Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination.

            Fragile-X syndrome is a common form of mental retardation resulting from the inability to produce the fragile-X mental retardation protein. Qualitative examination of human brain autopsy material has shown that fragile-X patients exhibit abnormal dendritic spine lengths and shapes on parieto-occipital neocortical pyramidal cells. Similar quantitative results have been obtained in fragile-X knockout mice, that have been engineered to lack the fragile-X mental retardation protein. Dendritic spines on layer V pyramidal cells of human temporal and visual cortices stained using the Golgi-Kopsch method were investigated. Quantitative analysis of dendritic spine length, morphology, and number was carried out on patients with fragile-X syndrome and normal age-matched controls. Fragile-X patients exhibited significantly more long dendritic spines and fewer short dendritic spines than did control subjects in both temporal and visual cortical areas. Similarly, fragile-X patients exhibited significantly more dendritic spines with an immature morphology and fewer with a more mature type morphology in both cortical areas. In addition, fragile-X patients had a higher density of dendritic spines than did controls on distal segments of apical and basilar dendrites in both cortical areas. Long dendritic spines with immature morphologies and elevated spine numbers are characteristic of early development or a lack of sensory experience. The fact that these characteristics are found in fragile-X patients throughout multiple cortical areas may suggest a global failure of normal dendritic spine maturation and or pruning during development that persists throughout adulthood. Copyright 2001 Wiley-Liss, Inc.
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              Object recognition memory and the rodent hippocampus.

              In rodents, the novel object recognition task (NOR) has become a benchmark task for assessing recognition memory. Yet, despite its widespread use, a consensus has not developed about which brain structures are important for task performance. We assessed both the anterograde and retrograde effects of hippocampal lesions on performance in the NOR task. Rats received 12 5-min exposures to two identical objects and then received either bilateral lesions of the hippocampus or sham surgery 1 d, 4 wk, or 8 wk after the final exposure. On a retention test 2 wk after surgery, the 1-d and 4-wk hippocampal lesion groups exhibited impaired object recognition memory. In contrast, the 8-wk hippocampal lesion group performed similarly to controls, and both groups exhibited a preference for the novel object. These same rats were then given four postoperative tests using unique object pairs and a 3-h delay between the exposure phase and the test phase. Hippocampal lesions produced moderate and reliable memory impairment. The results suggest that the hippocampus is important for object recognition memory.
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                Author and article information

                Contributors
                Journal
                Front Mol Neurosci
                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Media S.A.
                1662-5099
                02 October 2018
                2018
                : 11
                : 353
                Affiliations
                [1] 1Department of Clinical and Experimental Medicine, University of Messina , Messina, Italy
                [2] 2Department of Biomedical and Biotechnological Sciences, University of Catania , Catania, Italy
                [3] 3Oasi Research Institute, IRCCS , Troina, Italy
                [4] 4Institute of Neurological Sciences (ISN), National Research Council (CNR) , Catania, Italy
                [5] 5Department of Pharmacy — Drug Sciences, University of Bari , Bari, Italy
                Author notes

                Edited by: Regina Dahlhaus, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany

                Reviewed by: Niraj S. Desai, University of Texas at Austin, United States; Jean-Martin Beaulieu, University of Toronto, Canada; Hansen Wang, University of Toronto, Canada

                *Correspondence: Lucia Ciranna ciranna@ 123456unict.it
                Article
                10.3389/fnmol.2018.00353
                6176069
                30333723
                e6f850f9-b1fc-4574-9edb-ada3602038b1
                Copyright © 2018 Costa, Sardone, Bonaccorso, D’Antoni, Spatuzza, Gulisano, Tropea, Puzzo, Leopoldo, Lacivita, Catania and Ciranna.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 23 November 2017
                : 10 September 2018
                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 72, Pages: 14, Words: 10517
                Funding
                Funded by: Fondazione Telethon 10.13039/501100002426
                Award ID: GGP13145
                Funded by: FRAXA Research Foundation 10.13039/100000297
                Award ID: call 2013
                Categories
                Neuroscience
                Original Research

                Neurosciences
                serotonin,5-ht7 receptor,fragile x syndrome,cyclic amp,mglur-ltd,learning,pacap
                Neurosciences
                serotonin, 5-ht7 receptor, fragile x syndrome, cyclic amp, mglur-ltd, learning, pacap

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