New understanding of schizophrenia
A recent breakthrough study unearths a new mechanism of schizophrenia
Schizophrenia is a chronic brain disorder that affects approximately 1.1% of the adult population or roughly 51 million people worldwide. When schizophrenia is in its active form, symptoms can include delusions, hallucinations, disorganized speech or behaviour, trouble with thinking, loss of concentration and lack of motivation. Schizophrenia is now widely known but is very poorly understood and its exact cause is still not completely clear. Scientists worldwide believe that a combination of genetics, brain chemistry and environmental factors contributes together towards development and advancement of schizophrenia. These findings have been established after using advanced imaging to look at the brain’s structure and function. Also, schizophrenia cannot be prevented and no cure is available for it, though research is currently happening to develop new and safe treatments.
Early treatment of schizophrenia may help get the symptoms under control before any serious complications occur and can help to improve the long-term outcome for a patient. If a treatment plan is followed with care, it can help prevent relapses and also extreme worsening of the symptoms. New and effective therapies for an early diagnosis and treatment can hope to be developed once the risk factors for schizophrenia is clear. It has been proposed for quite some time that problems with certain naturally occurring chemicals in the brain – including neurotransmitters called dopamine and glutamate – may contribute to schizophrenia and also other mental illnesses. These ‘differences’ are seen in neuroimaging studies on brain and the central nervous system of people who have schizophrenia. The exact significance of these differences or changes is still not very clear, but it definitely indicates that schizophrenia is a brain disorder. Schizophrenia requires a lifelong treatment and even in those patients where symptoms appear to have subsided. Generally, a combined treatment of medications and psychosocial therapy can help manage the condition and only in severe cases hospitalization may be needed. A team effort by health professionals is needed in the clinics with expertise in schizophrenia treatment. Most antipsychotic medications for schizophrenia treatment are thought to control symptoms by affecting the brain neurotransmitter dopamine. Unfortunately, many such medications tend to cause serious side effects (which can include drowsiness, muscle spasms, dry mouth and blurred vision), making the patients reluctant to take them and in some cases injections may be the chosen route instead of taking a pill. Clearly, to develop therapeutic interventions and drugs to target and treat schizophrenia, it’s important to first understand the disorder by identifying all different possible mechanisms of actions.
A novel mechanism to understand and target schizophrenia
A recent study by neuroscientists from Case Western Reserve University School of Medicine, USA, led by Dr. Lin Mei, have uncovered a novel mechanism underlying the cause of schizophrenia. They have used genetic, electrophysiological, biochemical, and molecular techniques to uncover the function of a protein called neuregulin 3 (NRG3). This protein, belonging to the neuregulin protein family, has already been shown to be encoded by a ‘risk’ gene in various other mental illnesses including bipolar disorders and depression. And if we talk about schizophrenia, many variations in this particular gene (which encodes for NRG3) are considered as “major risk” factors. Several studies have been done on NRG3, but its exact and detailed physiological function is still very poorly understood. In this new study published in Proceedings of National Academy of Sciences, researchers while trying to uncover the potential function of NRG3, discovered that it is central to schizophrenia and could become a possible therapeutic target to treat it.
Researchers found that NRG3 protein mainly supresses a protein complex – which is very essential for proper neuron communication and the overall efficient working of the brain. The gene which encodes for NRG3 (so that it can effectively perform the function which it has to) was muted in mice in a certain number of neurons of the brain. Specifically, when the mutations were induced in the ‘pyramidal’ neurons – which play an important in activating the brain – mice displayed symptoms and behaviour in line with schizophrenia. The mice had healthy reflexes and also hearing capabilities, but showed unusual level of activity. They showed trouble in remembering (e.g. when navigating mazes) and also acted shy around stranger mice. Thus, it was clear that NRG3 plays a crucial role in schizophrenia and also the type of neurons involved were also defined. Further, researchers also uncovered how exactly this protein NRG3 works at the cellular level. It was seen that it basically inhibits an assembly of a complex of proteins at synapses – the place or junction where nerve cell or neurons communicate. The neurons need a complex (called SNARE, short for Soluble N-ethylmaleimide-sensitive factor activating protein receptor proteins), to transmit neurotransmitters (specifically glutamate) between each other at the synapses. People suffering from severe mental illnesses including schizophrenia, tend to have higher levels of NRG3 protein and these higher levels were responsible for supressing the release of glutamate – the naturally occurring neurotransmitter in the brain. This was seen in laboratory experiments that NRG3 could not form the ‘SNARE complex’ and thus glutamate levels were suppressed as a result of this.
Glutamate is abundant in the human body but is most prominently found in the brain. It is a highly ‘stimulatory’ or ‘excitatory’ neurotransmitter in our brain and is most critical for activating the neurons in the brain and thus essential for our learning, understanding and memory. This study concludes that NRG3 is very important for proper glutamate transmission in the brain and glutamate imbalances cause schizophrenic symptoms. Also, the function described here is detailed for the first time and very unique from previous roles described of this particular protein NRG3 as well as other proteins belonging to the same family.
Therapeutics in the future
Schizophrenia is a very devastating mental illness which drastically affects various areas of life. It disrupts the daily life by affecting day to day functioning, self-care, relationships with family and friends and all kinds of social life. The patients are generally not seen to have a particular ‘psychotic episode’ but rather overall life outlook and balances get affected. Coping with a mental disorder as serious as schizophrenia is extremely challenging, both for the person with the condition and for friends and family. Schizophrenia is considered as among the top 10 most disabling conditions. Since schizophrenia is very complex, clinical effect of medications are also varied in different patients and generally do not succeed beyond a few trials. New therapeutic treatments are urgently needed for this condition and this study has shown a new direction towards developing one.
The NRG3 protein can definitely serve as a new therapeutic target to help treat schizophrenia and possibly other mental illnesses like bipolar and depression. Drugs could be designed which can target NRG3 thereby help to restore glutamate levels in specific types of neurons and thus restore brain’s function during schizophrenia. This methodology can be a totally new approach towards treatment. This study has shed light on a novel cellular mechanism of schizophrenia and has generated immense hope in the field in mental illnesses. Though the path to discovering and launching effective drugs for treatment seems to appear very long at the moment, research is in the right direction at least.
Wang et al. 2018, ‘Controlling of glutamate release by neuregulin3 via inhibiting the assembly of the SNARE complex’, Proceedings of National Academy of Sciences, published ahead of print, DOI: 10.1073/pnas.1716322115