Chronic lithium administration down regulates transthyretin mRNA expression in rat choroid plexus

David J Pulford¹, Fiona Adams², Brian Henry², David J Mallinson², Ian C Reid³, Caroline A Stewart⁴

¹School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich, UK; ²Organon laboratories Ltd, Newhouse, UK; ³Department of Mental Health, Medical School Buildings, University of Aberdeen, UK; ⁴Section of Psychiatry and Behavioral Sciences, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, UK

Abstract: Transthyretin (TTR) accounts for a quarter of the protein content of ventricular cerebrospinal fluid (CSF) yet its exact role in the brain remains unknown. Patients with a diagnosis of depression have reduced CSF levels of TTR and the locus encoding the TTR gene has been implicated in a Danish pedigree of bipolar patients. Lithium, the major treatment for bipolar disorder in the UK, was subcutaneously infused into rats for 28 days in the form of lithium chloride using osmotic minipumps. In situ hybridizations using oligonucleotide probes targeted against the TTR transcript were performed on coronal brain sections. Lithium significantly reduced the level of transthyretin mRNA in the rat choroid plexus within the lateral and third ventricle. The down-regulation was confirmed using semi-quantitative reverse transcription PCR on dissected brain tissue. Recent studies in mice suggest that the TTR gene is implicated in depression-like behavior therefore this effect of lithium may be relevant to its use as a mood stabilizer or an adjuvant to antidepressant drugs.

Keywords: bipolar disorder, in-situ hybridization, mood stabilizer, minipump, (SQ)-RT-PCR