Bipolar disorder is an often debilitating mental illness that affects tens of millions of people worldwide. New research may have uncovered a protein deficiency that causes the disease, in a breakthrough that could inform future treatment options.
Bipolar disorder (BD) – also known as manic-depressive disorder – affects approximately 60 million people around the globe, and 2.6 percent of adults in the United States. The overwhelming majority of these cases are considered severe.
People living with BD are affected by drastic changes in mood and energy levels to a degree that interferes with their daily activities.
The causes of BD remain unknown, but previous research has forayed into the genetic background of the illness. For instance, the gene that encodes the cellular protein phospholipase Cγ1 has been linked to BD, although the exact mechanism that causes the disorder was unknown until now.
New research from the Ulsan National Institute of Science and Technology (UNIST) in Ulsan, South Korea, has tested the role of phospholipase Cγ1 (PLCγ1) in mice, and the findings may help to explain the causative link between the protein and BD.
PLCγ1-deficiency in mice causes bipolar disorder
Researchers, led by Pann-Ghill Suh, a professor of life sciences at UNIST, genetically designed mice to have a deficiency of PLCγ1 in their forebrain. They then studied what happened in the mice’s synapses – the ends of neurons, which facilitate electric signaling between two brain cells.
Scientists noticed impairment in the inhibitory transmission and synaptic plasticity – that is, the synapses’ ability to change their shape, function, or strength over time.
The brain-derived neurotrophic factor (BDNF) is a protein that regulates several synaptic functions, including the activity of PLCγ1. BDNF is crucial in synapse formation, and in this study, the BDNF deficits led to an imbalance between excitatory and inhibitory transmission between the brain cells’ synapses.
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The result, as noticed by Suh and team, was that PLCγ1-deprived mice displayed BD-like symptoms, including hyperactivity, reduced anxiety-like behavior, abnormally high feelings of pleasure (hyperhedonia), excessive hunger, and impaired learning and memory, as well as abnormally high startle responses.
Researchers administered drug treatment for BD to these mice and this reduced their symptoms.
To sum up, there appears to be a neurochemical chain reaction that leads to the disease. The synapses that do not have enough PLCγ1 are unable to fulfill their inhibitory function properly in excitatory neurons, because the BDNF is not working properly either. This causes a disproportion between excitatory synapses and inhibitory ones, eventually leading to bipolar symptoms.
Prof. Suh explains the findings:
“In the brain, excitatory synapses and inhibitory synapses work together to remain balanced for proper neurotransmission. Our study demonstrated that the imbalance between these two is a major cause of various neuropsychiatric disorders and the […] dysfunction observed in the hippocampi of bipolar disorder patients.”
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Until now, although the PLCγ1 gene had been suggested to play a role in BD, it was unclear exactly how PLCγ1 affected interneuronal signaling and how it caused mental illness.
“After 10 years of research, we have finally revealed PLCγ1 protein plays a major role in the onset of bipolar disorder,” Suh adds. “Our findings, therefore, provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.”
The breakthrough is likely to influence research into the treatment of BD and its symptoms.