NCAM-deficient mice show prominent abnormalities in serotonergic and BDNF systems in brain - Restoration by chronic amitriptyline.
Mood disorders are associated with alterations in serotonergic system, deficient BDNF (brain-derived neurotrophic factor) signaling and abnormal synaptic plasticity. Increased degradation and reduced functions of NCAM (neural cell adhesion molecule) have recently been associated with depression and NCAM deficient mice show depression-related behavior and impaired learning. The aim of the present study was to investigate potential changes in serotonergic and BDNF systems in NCAM knock-out mice. Serotonergic nerve fiber density and SERT (serotonin transporter) protein levels were robustly reduced in the hippocampus, prefrontal cortex and basolateral amygdala of adult NCAM(-)(/-) mice. This SERT reduction was already evident during early postnatal development. [(3)H]MADAM binding experiments further demonstrated reduced availability of SERT in cell membranes of NCAM(-)(/-) mice. Moreover, the levels of serotonin and its major metabolite 5-HIAA were down regulated in the brains of NCAM(-)(/-) mice. NCAM(-)(/-) mice also showed a dramatic reduction in the BDNF protein levels in the hippocampus and prefrontal cortex. This BDNF deficiency was associated with reduced phosphorylation of its receptor TrkB. Importantly, chronic administration of antidepressant amitriptyline partially or completely restored these changes in serotonergic and BDNF systems, respectively. In conclusion, NCAM deficiency lead to prominent and persistent abnormalities in brain serotonergic and BDNF systems, which likely contributes to the behavioral and neurobiological phenotype of NCAM(-/-) mice.
Institute of Biomedicine and Translational Medicine, Department of Pharmacology, University of Tartu, 50411 Tartu, Estonia. Electronic address: anu.aonurm@ut.ee.
Anu
A
Aonurm-Helm
Institute of Biomedicine and Translational Medicine, Department of Pharmacology, University of Tartu, 50411 Tartu, Estonia.
Kaili
K
Anier
Institute of Biomedicine and Translational Medicine, Department of Pharmacology, University of Tartu, 50411 Tartu, Estonia.
Tamara
T
Zharkovsky
Neuroscience Center, University of Helsinki, P.O. Box 56, Helsinki, Finland.
Eero
E
Castrén
Neuroscience Center, University of Helsinki, P.O. Box 56, Helsinki, Finland.
Tomi
T
Rantamäki
Institute of Chemistry, University of Tartu, 50411 Tartu, Estonia.
Vladimir
V
Stepanov
Institute of Chemistry, University of Tartu, 50411 Tartu, Estonia.
Jaak
J
Järv
Institute of Biomedicine and Translational Medicine, Department of Pharmacology, University of Tartu, 50411 Tartu, Estonia.
Alexander
A
Zharkovsky
D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use*; D000639:Amitriptyline / Q000627:therapeutic use*; D000818:Animals; D001921:Brain / Q000378:metabolism; D001928:Brain Diseases, Metabolic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D004195:Disease Models, Animal; D055664:Electrochemical Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019006:Neural Cell Adhesion Molecules / Q000172:deficiency* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D020813:Receptor, trkB / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
D018759:Adrenergic Uptake Inhibitors; D019208:Brain-Derived Neurotrophic Factor; D019006:Neural Cell Adhesion Molecules; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D000639:Amitriptyline; D012701:Serotonin; D020813:Receptor, trkB
Antidepressant; Neurotrophins; Plasticity; Serotonergic neurotransmission