Staglin Family / IMHRO Assistant Professor of Psychiatry, UCSF

Right now you are reading an article on a computer screen. The patterns of the letters are flowing from your eyes to your brain, their shapes being processed by the thalamus and their meanings by the hippocampus, and a combination of information from these two centers is flowing to your prefrontal cortex so that—voila! You know and understand what you have read. If you have a thought disorder, however, this process may be jumbled. Current theory has it that the thought disorder inherent in schizophrenia may be due to an imbalance in the signal transmission between these three parts of the brain, and IMHRO-sponsored Assistant Professor Susan Voglmaier, M.D., Ph.D. of UCSF is working on a study that may help to decode why and how to treat it.

When electrochemical signals travel through the brain, they cross synapses, or gaps between neurons, by means of chemicals called neurotransmitters. Glutamate, one of these, can excite the activity of connected neurons. As Dr. Voglmaier explains, "glutamate is released from a pre-synaptic neuron in response to stimulation, then is recycled back into the neuron, and is repackaged by means of 'transporter' proteins called VGLUTs. If too much or too little glutamate is present in the synaptic gap, the post-synaptic neuron can be over- or under-stimulated—leading sometimes to too strong or weak a signal—and an imbalance among the brain pathways that let you see and understand the world. As Dr. Voglmaier explains, "VGLUT2 is expressed in thalamo-cortical pathways, which carry sensory information, and VGLUT1 is expressed in cortico-cortical pathways, which carry information reflecting the state of the organism and its expectations of the external world... Impairments in the timing or integration of VGLUT2 thalamocortical and VGLUT1 cortico-cortical afferents may lead to misinterpretation of the external origin of perceptions and conceptualizations, resulting in confusion and psychosis."

This year, she and her lab have started to uncover potentially useful ways in which these transporters' operations differ in these two circuits. Specifically, she has found that VGLUTs 1 and 2 recycle glutamate differently in response to neuroelectrical stimulation. (Previously it had been widely thought that all such transporters recycled the same way.) Now, Dr. Voglmaier's lab is carefully studying the structure of these 2 proteins to see why this is so. Already she's found that removing a small section of VGLUT1 actually speeds recycling.  Also, as she explains, "inhibition of a novel trafficking pathway mitigates the differences between VGLUT1 and 2 recycling." Perhaps, as she suggests, these effects can be harnessed to someday better balance the brain's perceptual processing with new antipsychotic medications.

Now, Dr. Voglmaier's lab is developing techniques to proceed along this path. As of 2008 they had constructed a fluorescent VGLUT, which when implanted into a mouse via an artificial chromosome, could cause the mouse's neurons to glow when releasing glutamate. Her lab has succeeded in genetically engineering a cohort of mice that has this VGLUT in their brains for study. Using novel microscopic techniques, she and her lab hope to soon be able to actually watch the activity of synapses in live mice—and trace this activity across their brains' glutamate pathways. She is also conducting parallel research on pathways involving GABA, another neurotransmitter, which works to inhibit neuronal activity. When she and her lab are able to observe these neurotransmitter pathways in action, even more valuable clues to targeted thought disorder therapies may turn up.

If you'd like to meet Dr. Voglmaier and ask her about her research, please come to the free scientific symposium at the Staglin Music Festival for Mental Health on September 11, 2010. She will be there and will be available to answer your questions.

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