A Research Blog

Events at synaptic terminal underlying glutamate releaseFirst steps taken in understanding psychiatric disorders

A team from Duke-NUS Medical School and the National University of Singapore discovered how a major susceptibility gene for mental illness – Disrupted-In-Schizophrenia-1 (DISC1) – regulates glutamate release and neurotransmission across synapses. This discovery provides welcome progress to the development of targeted therapies for mental illness, a field facing decline as it has been plagued by detrimental side effects, high costs, and the inability to develop treatments to treat the disease rather than just the symptoms.

Glutamate is the main excitatory neurotransmitter in the brain. The release of glutamate from nerve terminals into the synaptic cleft underlies neuron-to-neuron communication in brain regions involved in higher cognitive functions, such as learning and memory, executive planning, and mental imagery. Not surprisingly, abnormal glutamate neurotransmission is linked to major psychiatric diseases, like schizophrenia, autism and bipolar disorder. However, pinpointing the cause of abnormal neurotransmitter release in these mental illnesses has been elusive.

Although rare, DISC1 mutations are associated with high risk for major psychiatric disorders, and raises the possibility of DISC1 involvement in neurotransmitter release. Using an optical probe, Asst Prof Marc Fivaz’s team collected data on the speed of glutamate release from thousands of control and DISC1 mutant nerve terminals. In a rare collaboration between the Neuroscience and Behavioural Disorders and Health Services and Systems Research Programmes, the data collected was then analysed by Asst Prof Marcel Bilger using methods normally applied in econometrics. It was found that DISC1 accelerates glutamate release at nerve terminals. The team went on to show that this boosting effect is mediated by an important class of calcium channels named Cav2.2, that initiates glutamate release and neurotransmission.

Imaging glutamate release at individual synaptic terminals. (Image credit: Tang W, et al. Front Synaptic Neurosci.)These latest results uncover a central function of the DISC1 gene in regulating neurotransmitter release. They also suggest that this process, when disrupted, could lead to deficits in working memory and moment-to-moment processing of information – two cardinal features of schizophrenia. Importantly, these findings also identify the calcium channel Cav2.2 as a potential therapeutic target for the treatment of major mental illnesses. As we start to unravel the disease mechanisms underlying mental illnesses, the prospect of developing novel disease-modifying therapeutics is becoming a reality.

You can read more about this study here.  

This work was supported by a grant from the Ministry of Education Academic Research Fund (MOE2013-T2-1-053).

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