Lecture 26: Bipolar Disease and Lithium

What is bipolar disorder?

a chronic recurrent mood disorder consisting of repeated episodes of mania or mixed episode of mania and depression

What is mania?

a distinct period of abnormally elevated or irritable mood and shows symptoms including inflated self-esteem, psychosis, increased talkativeness and activity, decreased need of sleep, racing thoughts, distractibility, and impaired judgement

What is depression?

a chronic period of feeling of sadness, loss, anger, or worthless that is severe enough to hinder daily activities (including feeding and sleep) and induce suicidal thoughts

True or False: Bipolar disorder is a common disorder but its cause is elusive.

true

What is the prevalence of bipolar disorder?

• affects an estimated 2.8% of U.S. adults

• 1 in 226 people worldwide

True or False: Bipolar disorder is associated with a 15-fold higher suicide risk than the general population.

true

What are the biological differences in bipolar disorder?

• physical changes in the brain

• reduced gray/white matter volume and thinner cortices

• reduced dendritic spine density and dendrite complexity

What are the risk factors of bipolar disorder?

• family history

• periods of high stress

• drug or alcohol misuse

What are the lifelong treatments of bipolar disorder?

• medicines

• intensive outpatient programs

• hospital stays

• treatment for alcohol or drug misuse

What are the types of medications to treat BD?

• mood stabilizers: lithium, carbazepine, lamotrigine, and valproic acid

• antipsychotics: olanzapine and lumateperone

• antidepressants: fluoxetine

• antidepressant-antipsychotic combination: symbax

• antianxiety medicines: benzodiazepines

Is there a cure for BD?

unfortunately there is not

True or False: Although the current treatment and service options can improve symptoms and daily functioning of the people with BD, the BD is a lifelong disorder and the people with BD faces continuous challenges with high risk of suicidal thoughts.

true

True or False: Lithium is a first-line treatment for BD.

true

What are the pros of lithium?

• reduces mania and depression

• decreases suicide risk in BD patients

• normalizes the BD-associated reductions in dendrite complexity and dendritic spine density

What are the cons of lithium?

• less than 1/3 of patients respond to lithium

• side effects such as weight gain, cognitive and kidney deficits

• precise molecular targets remain elusive

What does lithium activate and inhibit?

• GSK3B auto-inhibition

• cAMP/PKA signaling activation

What does post-mortem BD cortex and BD patient-derived hiPSC neurons show?

reduced dendritic spine density, spine length, and dendrite complexity

Where did genome-wide association studies (GWASs) for BD find multiple single nucleotide polymorphisms (SNPs)?

in the upstream region of the ANK3 gene which encodes Ankyrin-G (AnkG)

Where are AnkG-480 and AnkG-270 enriched?

• axon initial segment

• nodes of Ranvier

• GABAergic synapses

Where is AnkG-190 enriched?

dendrites and dendritic spines

What does AnkG-190 maintain?

dendritic spine and dendritic arbor stability

What are dendritic spines?

postsynaptic dendritic protrusions that house excitatory synapses

True or False: Dendritic spine density, width and length, together with dendritic arbor complexity (length and branches) are the structural substrate of cortical connectivity and are altered across many neuropsychiatric diseases.

true

What do Ank3 KO mice mimic?

BD behavioral features (elevated locomotor activity, reduced anxiety, repetitive behavior, sleep impairment, social defeat stress-induced mood switching from mania to depression)

Do Ank3 KO mice respond well to lithium treatment?

yes, they do

What is unknown or the gap in the field of this particular subject/disease?

• unknown role of Ank3 in neuronal structure

• lithium’s cellular mechanism

• mechanisms of lithium action

• lithium responsiveness

• future gap identified by authors

• biomarker gap

What was the central hypothesis?

the authors hypothesized that Ank3 deficiency causes dendritic abnormalities relevant to bipolar disorder and that lithium rescues these defects through synergistic regulation of the GSKB and cAMP signaling pathways

What was the method to test the central hypothesis in this paper?

• conditional Ank3 KO or control ± chronic lithium carbonate chow

• AnkG knockdown (RNAi) in rat primary cortical neuronal culture

• pharmacology treatment

Does Ank4 KO disrupt dendritic complexity and spine density?

• genetic deletion of Ank3 in CaMK2a-expressing excitatory glutamatergic pyramidal neurons decreases spine density and the number of intersections of basal dendrites

• Ank3 RNAi knock-down decreases interactions of total dendrites due to basal dendrites

Ank3 RNAi knock-down decreases interactions of total dendrites due to basal dendrites. What is this effect blocked by?

coexpression with AnkG-190 but not AnkG-270

Can chronic lithium treatment rescue the dendritic deficits?

yes, partially to substantially rescues the dendritic deficits, including reduced spine density and decreased basal dendritic complexity in Ank3-deficient mice

Does lithium rescue spine and dendrite deficits in vitro?

Ank3 KD decreases spine density, width and length as well as basal dendrite intersections compared to control, whereas lithium treatment blocks these effects of Ank3 KD

Does lithium restore dendritic complexity and spine density via GSK3B?

CHIR99021 treatment rescues spine width and length but not spine density nor dendritic complexity

Does lithium restore dendritic complexity and spine density via cAMP pathways?

• forskolin alone rescues basal dendrite complexity but has no effect on spines

• CHIR99021 and forskolin together rescue spine density and basal dendrite complexity

True or False: Lithium blocks Ank3 KD-induced decreases in spine density, width, and length.

true

Are GSK3B and PKA signaling necessary for the lithium rescue?

• this lithium effect on spine density was inhibited upon GSK3B-S9A expression or PKA inhibition, suggesting that both GSK3B inhibition and PKA activation are necessary

• this lithium rescue of spine width and length was blocked by GSK3B-S9A and GSK3B-S9A+PKA inhibition but not PKA inhibition, suggesting that GSK3B inhibition is necessary for spine width/length rescue

• this lithium effect was inhibited upon PKA inhibition alone or PKA inhibition with GSK3B-S9A expression but not GSK3B-S9A expression alone, suggesting that PKA activation is necessary for lithium-mediated rescue of basal dendrite complexity

Did the authors prove their hypothesis?

• the authors largely supported their hypothesis: Ank3 deficiency caused dendritic and spine deficits, lithium rescued these abnormalities, and the rescue involved synergistic actions of the GSK3B and cAMP pathways

• additional in vivo studies are needed to fully establish the mechanism and behavioral relevance

What is the significance of the paper?

this study provides a mechanistic link between Ank3 dysfunction, dendritic abnormalities, and bipolar disorder, while identifying GSK3B and cAMP signaling pathways as key mediators of lithium’s therapeutic effects and potential targets for future treatments

What is the future direction of this paper?

future studies should test the GSK3B/cAMP mechanism in vivo, connect dendritic rescue to behavioral recovery, identify biomarkers of lithium response, and develop targeted therapies that mimic lithium’s effects with fewer side effects