Lithium-associated transcriptional regulation of CRMP1 in patient-derived olfactory neurons and symptom changes in bipolar disorder

Abstract

There is growing evidence that lithium used in the treatment of bipolar disorder (BD) affects molecular targets that are involved in neuronal growth, survival, and maturation, but it remains unclear if neuronal alterations in any of these molecules predict specific symptom changes in BD patients undergoing lithium monotherapy. The goals of this study were to (a) determine which molecular changes in the olfactory neurons of symptomatic patients receiving lithium are associated with antimanic or antidepressant response, and (b) uncover novel intraneuronal regulatory mechanisms of lithium therapy. Twenty-two treatment-naïve non-smoking patients, with symptomatic BD underwent nasal biopsies for collection of olfactory tissues, prior to their treatment and following a 6-week course of lithium monotherapy. Sixteen healthy controls were also biopsied. Combining laser capture microdissection with real-time polymerase chain reaction, we investigated baseline and treatment-associated transcriptional changes in candidate molecular targets of lithium action in the olfactory neuroepithelium. Baseline mRNA levels of glycogen synthase kinase 3 beta (GSK3β) and collapsin response mediator protein 1 (CRMP1) genes were significantly associated with BD status and with severity of mood symptoms. Among BD subjects, treatment-associated downregulation of CRMP1 expression was most predictive of decreases in both manic and depressive symptoms. This study provides a novel insight into the relevance of CRMP1, a key molecule in semaphorin-3A signaling during neurodevelopment, in the molecular mechanism of action of lithium, and in the pathophysiology of BD. It supports the use of human-derived olfactory neuronal tissues in the evaluation of treatment response of psychiatric disorders.