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The Neurobiological Mechanisms of Bipolar Disorder

By: Sai Srihaas Potu

Bipolar disorder is a chronic psychiatric condition characterized by mood swings with both manic and depressive symptoms. There is increasing evidence that bipolar disorder is a neuroprogressive disorder, meaning that longer duration of the disease entails more pronounced changes at the clinical and neuropathological level.

Bipolar disorder is a persistent, episodic, and debilitating condition with an estimated lifetime prevalence of over 2.0%, including both type I and II. Bipolar disorder is associated with recurring episodes of psychosis, depression, as well as prevalent anxiety symptoms—all leading to high risks of potentially severe functional impairment, substance abuse, and high rates of suicide—all despite the use of available pharmacological and psychosocial treatments.

Manic episodes are associated with bipolar I and cause individuals to engage in risky or reckless behavior. An individual experiencing a hypomanic episode may experience similar symptoms but their functioning will not be impaired. Many individuals who experience hypomania associated with bipolar II enjoy the increase in energy and decreased need for sleep.

Researchers from Tufts have gained new insight into a protein associated with bipolar disorder. The study reveals that calcium channels in resting neurons activate the breakdown of Sp4, which belongs to a class of proteins called transcription factors that regulate gene expression.

This study, led by Grace Gill, identifies a molecular mechanism regulating Sp4 activity. Her previous research had determined that reduced levels of Sp4 in the brain are associated with bipolar disorder. Her work overall suggests that the misregulation of Sp4 may contribute to the development of bipolar disorder. Understanding how transcription factors like Sp4 are regulated may provide us with ways to change neuronal gene expression to treat symptoms of mental illness, including bipolar disorder.

The main goal of the study was to determine whether a specific type of calcium channel drives the breakdown of the Sp4 protein. Along the way, however, the research team also discovered that signaling by these calcium channels is most active in the so-called off or resting phase. The calcium-signaling regulation of Sp4 during the resting phase was unexpected and suggests two things: resting neurons are more active than we had thought and calcium signaling influences gene expression in both active and resting neurons.

In neurons, cells that can be stimulated by electrical signals, transcription factors are regulated by calcium entry that is initiated when the cell depolarizes. Depolarization occurs when the overall voltage of the cell is increased. This is the on or active state for the cell. In contrast, when the cell’s voltage is decreased, hyperpolarization occurs. This is called the off or resting phase for the cell.

Store-operated calcium channels (SOCC) are a type of calcium channel found in all cells. These channels are activated when stores of calcium inside the cell are reduced. A calcium sensor called stromal interaction molecule 1 (STIM1) is responsible for calcium entry into the cell through SOCCs.

To determine whether STIM1 controlled Sp4 breakdown, the researchers reduced STIM1 levels in cells and measured Sp4 levels. A control group of cells contained normal levels of STIM1, while a comparison group contained reduced STIM1 levels. Both cell groups were placed in a solution for 60 minutes to move them into their resting state.

The cells in the control group displayed significantly less Sp4 when at rest while, in contrast, cells in the comparison group – those with reduced STIM1 levels – had higher Sp4 levels. These findings provide evidence that STIM1 is required for the breakdown of Sp4 when the cell hyperpolarizes, which tells us that the presence of STIM1 directly influences Sp4 levels in neurons.

Some of Gill’s previous research, performed in collaboration with researchers from Spain, found that Sp4 levels were lower in two areas of the brain in postmortem samples from patients with bipolar disorder. In a recent study, she and her team determined that one mechanism of Sp4 regulation is a glutamate receptor called the NMDA receptor.

Bipolar disorder is a prevalent condition with a very large disease burden that includes high social and economic costs, substance abuse, disability, high suicidal risks, and especially poor control of depressive components of the disorder. Despite its high prevalence of treatment-resistance, studies of pharmacological treatment options in bipolar disorder remain remarkably scarce and largely inconclusive.

A considerable challenge in the management and treatment of bipolar disorder is the fact that it can take upwards of ten years for an individual with bipolar disorder to receive an accurate diagnosis, and over 60% of bipolar individuals report being initially misdiagnosed as having unipolar depression. There are considerable challenges to using biological markers in a clinical setting for assessment and diagnostic purposes. These challenges involve the expense and technical demands of neuroimaging, as well as the poor precision with which neuroimaging data can classify and predict individual behavior.

It will be important for researchers and clinicians to directly address these challenges if neuroscience techniques are to eventually facilitate diagnostic assessment. Lastly, research on reward-related neural activation in bipolar disorder has important pharmacological and psychosocial treatment implications.

The depressive components of the disorder have been especially difficult to treat successfully and they account for three-quarters of the nearly 50% of weeks of follow-up with treatment that includes clinically significant residual morbidity. Further research needs to be conducted to better understand the neurobiological mechanisms of bipolar disorder. This will allow researchers to better understand the cause of the disorder and develop new cures that are more reliable and accessible.


1. Goldberg JF, Chengappa KN. Identifying and treating cognitive impairment in bipolar disorder. Bipolar Disorders. 2009.

2. Gregory Saia, Jasmin Lalonde, Xinxin Sun, Belén Ramos, Grace Gill. Phosphorylation of the transcription factor Sp4 is reduced by NMDA receptor signaling. Journal of Neurochemistry. 2014.

3. Lalonde J, Saia G, Gill G. Store-Operated Calcium Entry Promotes the Degradation of the Transcription Factor Sp4 in Resting Neurons. Science Signaling. 2014.

4. Nurnberger JI, Koller DL, Jung J, Edenberg HJ, Foroud T, Guella I. Identification of pathways for bipolar disorder: a meta-analysis. JAMA Psychiatry. 2014.


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