5-HT receptor-mediated modulation of glutamate transmission in the hippocampus and prefrontal cortex and its relation to cognition and depression

Depression is a multifaceted disease which is marked by cognitive and emotional memory impairments. It is characterised by an imbalacement of serotonergic and glutamatergic system in brain areas such as hippocampus and prefontal cortex. Current antidepressant treatments available on the market and newer candidates need a better understanding of their mechanism of action, both at behavioral and molecular level. During my PhD thesis I have tested several hypothesis: In paper I – 5-HT7 receptors are involved in emotional memory caused by a direct or indirect activation of the receptor. This was tested in the passive avoidance (PA) task where systemic administration of the dual 5-HT1AR/5-HT7R agonist, 8-OHDPAT, was combined with 5-HT1AR and 5-HT7R antagonists administration in mice. Local infusion of 8-OH-DPAT was administered into the dorsal hippocampus in order to delineate that 5-HT1AR and 5-HT7Rs potentially crosstalk in hippocampal processing of emotional memory. In paper II – lurasidone, a second generation antipsychotic, posesses antidepressive properties, similar to the well studied fluoxetine, a selective serotonin reuptake inhibitor (SSRI). Chronic effects of lurasidone and fluoxetine were tested using behavioral approaches, such as novelty induced hyponeophagia (NIH), as well as immunobloting measurements in hippocampal and prefrontal cortex areas. In paper III – 5-HT1BR and p11 interaction affects the hippocampal neurotransmission. This was tested using biosensors to measure in vivo glutamate release with fast analytical sensing technology (FAST). Immunoblotting measurements were also performed, to determine glutamate receptor phosphorylation. Moreover, neurochemical events associated with p11-mediated regulation of 5-HT1BR function were tested by a non-invasive methodology, in vivo proton magnetic resonance spectroscopy (H-MRS) recordings. In paper IV – N methyl-D-aspartate receptor (NMDAR) antagonists, ketamine and Ro25-6981, compunds with rapid antidepressive properties, modulate glutamate release. This was tested with FAST-subsecond glutamate release mesurements in hippocampal-prefrontal cortex circuitry. In conclusion, the work conducted in this thesis has contributed in understanding the interaction between serotonergic and glutamatergic systems in hippocampal and prefrontal cortex areas, providing novel insights upon mechanism of action of different classes of antidepressants reflected both at the behavioral and molecular level. LIST OF SCIENTIFIC PAPERS Eriksson TM, Holst S, Stan TL, Hager T, Sjogren B, Ogren SO, Svenningsson P, Stiedl O. 5-HT1A and 5-HT7 receptor crosstalk in the regulation of emotional memory: implications for effects of selective serotonin reuptake inhibitors. Neuropharmacology, 2012; 63(6):1150-60. Stan TL, Sousa VC, Zhang X, Ono M, Svenningsson P. Similar effects of lurasidone and fluoxetine on novelty-induced hypophagia and regulation of NMDA receptor-subunits. Manuscript draft, 2014. Eriksson TM , Alvarsson A, Stan TL, Zhang X, Hascup KN, Hascup ER, Kehr J, Gerhardt GA, Warner-Schmidt J, Arango-Lievano M, Kaplitt MG, Ogren SO, Greengard P, Svenningsson P. Bidirectional regulation of emotional memory by 5-HT1B receptors involves hippocampal p11. Molecular Psychiatry, 2013;18: 1096–1105. Stan TL, Alvarsson A, Branzell N, Sousa VC, Svenningsson P. NMDA receptor antagonists ketamine and Ro25-6981inhibit evoked release of glutamate in vivo.Translational Psychiatry, 2014; 4, e395. LIST OF ABBREVIATIONS aCSF Artificial cerebro-spinal fluid AMPAR Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor APV D-(-)-2-amino-5-phosphonopentanoic acid Arc Activity-regulated cytoskeletal-associated protein ATP Adenosine triphosphate BDNF Brain-derived neurotrophic factor BD Bipolar disorder BS Bursting spiking Ca2+ Calcium ions Cr Creatine CAMKII Calcium2+/calmodulin-dependent protein kinase II EEAT1/EEAT2 Excitatory amino acid transporter 1/2 EEG Electroencephalography et al et alibi, and others etc et cetera, and other things DAG Diacylglycerol DG Dentate gyrus DRN Dorsal raphe nuclei DSMIV Diagnostic and Statistical Manual of Mental Disorders, 4 edition F20 Fluoxetine 20 mg/kg GABA γ-aminobutyric acid