Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: preliminary studies

Abstract

Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30–40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of “clock genes” and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low-amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.

Neurobiological and behavioral mechanisms of circadian rhythm disruption in bipolar disorder: A critical multi‐disciplinary literature review and agenda for future research from the ISBD task force on chronobiology

“…222 Using peripheral cell cultures and iPSC-derived neurons, circadian rhythm abnormalities have been described in BD, including anomalies in clock gene expression, 223 period, 135,180 phase, 181 and low amplitude. 181,224,225 Similar studies have revealed cellular rhythm abnormalities in SCHZ, 226 alcoholism, 227 Alzheimer's Disease, 228 and ADHD. 229 However, none of these cell-based studies have compared two or more clinical samples directly, and some of the differences in rhythms parameters are distinct.…”

A functional SNP rs895819 on pre-miR-27a is associated with bipolar disorder by targeting NCAM1

“…Western blotting of a miR-27a KO cell model and function analysis validated NCAM1 as a direct target in human NPCs. While NPCs 46 play critical roles in bipolar disorder, aberrant neuron functions might also be related to bipolar disorder 47 . Previous studies have identified associations of serum microRNA-27a with cognitive function in a Japanese population 48 and found that NCAM is elevated in the CSF of patients with bipolar type I and unipolar affective disorders 49 .…”

Mood Stabilizers in Psychiatric Disorders and Mechanisms Learnt from In Vitro Model Systems

“…They observed strong circadian rhythms in Per2-luc expression in NPCs and neurons of LR and controls, but NPC rhythms in LR were shorter whereas NR rhythms were weak and low in amplitude. They found that lithium lengthened the circadian time period in LR and control neurons, but failed to change the rhythms in the lithium NR group [132].…”