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John Forbes Nash, Jr.
Image courtesy of Princeton University.

“I felt like I might get divine revelation by seeing a certain number; a great coincidence could be interpreted as a message from heaven.”

– John Nash in “A Brilliant Madness”

John Forbes Nash Jr. was a 20-year-old graduate student when he came up with the mathematical theories that would win him the Nobel Prize in Economics 50 years later. His mathematical insight into game theory is often over-shadowed by accounts of the eccentric behavior, paranoia, and delusions that characterized his schizophrenia. Paranoid schizophrenia manifests in clinical terms as fixed beliefs that are over-imaginative and accompanied by experiences of hauntingly real perceptions of something not actually present. These hallucinations often take the form of auditory or visual disturbances and can be accompanied by a lack of motivation and clinical depression. In his own words in the documentary “A Brilliant Madness,” Nash admits that his schizophrenia was an escape that enabled him to feel exhilarated believing he was the most important person in the world who at any moment might have a rush of messages bringing him mathematical insight.

How do scientists even begin to unravel what is occurring in the brain of an individual whose perception of the external world does not reflect reality? With the identification of several susceptibility genes, scientists have implicated malformations in synapse development as an underlying factor in schizophrenia. Monday’s article introduced Neuregulin-1 (NRG-1) as a gene whose mutated form has been associated with schizophrenia as a result of disrupting synaptic plasticity. Post-mortem brain analysis of patients with schizophrenia has also identified synaptophysin a SNARE-interacting protein to be reduced in several key brain regions that regulate learning and higher order cognitive function [1]. Synaptophysin is the most abundant synaptic vesicle protein and is capable of regulating endocytosis of synaptic vesicles both during and after sustained neuronal activity [2]. Neurons communicate at contact sites called synapses. At pre-synaptic sites,  neurotransmitterChemicals that cross some synapses and carry a signal to the... More is released from synaptic vesicles, which fuse at a specific region of the membrane called the active zone. The SNARE complex and its regulator synaptophysin help the vesicle fuse to the plasma membrane so that chemical communication can occur at the synapseConnections between neurons where a signal is passed from on... More.

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Decision-making and interpretation of stimuli from the environment is dependent on successful communication between neurons. It is remarkable that neurons can sustain rapid rates of synaptic transmission without exhausting their supply of synaptic vesicles. Recycling is not just great for the environment; it is also crucial process in our brains that enable synaptic vesicles to be reused for hundreds, possibly thousands of cycles. As outlined in the figure below, synapses have developed efficient mechanisms to recapture and reuse membranes that have fused with the plasma membrane to release neurotransmitters.

Docked and primed synaptic vesicles make up the readily releasable pool. Following calcium influx they undergo exocytosis and release neurotransmitters into the synaptic cleft. The neurotransmitters can activate post-synaptic receptors. Endocytosis is the process that enables synaptic vesicles to return to the recycling pool. Image adapted from Haucke et al., 2011 [3].
Docked and primed synaptic vesicles make up the readily releasable pool. Following calcium influx they undergo exocytosis and release neurotransmitters into the synaptic cleft. The neurotransmitters can activate post-synaptic receptors. Endocytosis is the process that enables synaptic vesicles to return to the recycling pool.
Schizophrenia continues to be described as a disease of neuronal connectivity. It is thought that disturbances of synaptic connectivity arise both by disrupted synaptic transmission in adulthood and abnormalities in controlling synaptic connectivity during development of the central nervous systemThe brain and spinal cord.. The integral role of the SNARE complex in endocytosis makes it a candidate for understanding how disruptions in a specific synaptic protein might influence aberrant synaptic transmission.

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References:

1. Johnson RD, Oliver PL, and Davies KE (2008) SNARE proteins and schizophrenia: linking synaptic and neurodevelopmental hypotheses. Acta biochimica Polonica 55: 619-628.

2. Kwon SE and Chapman ER (2011) Synaptophysin regulates the kinetics of synaptic vesicle endocytosis in central neurons. NeuronThe functional unit of the nervous system, a nerve cell that... More 70: 847-854.

3. Haucke V, Neher E, and Sigrist SJ (2011) Protein scaffolds in the coupling of synaptic exocytosis and endocytosis. Nature reviews Neuroscience 12: 127-138.

Images adapted from PNAS Classics and Cell Signal.

Jillian L. Shaw

Jillian decided to dedicate herself to a life of exploring the mysteries of the brain after reading neurological case studies by Oliver Sachs and Ramachandran as a student at Vassar College.After completing a B.A. in Neuroscience with honors in 2009, Jillian headed to USC to pursue a Ph.D. in Neuroscience where she is now in her 5th year.A research stint in Belgium exposed Jillian to the complexities of cell signaling pathways, and her interests shifted from cognitive neuroscience to cellular and molecular neuroscience.Her current research focuses on the link between Down syndrome and Alzheimer’s disease using Drosophila as a genetic model to explore axonal transport, mitochondria dysfunction, synaptic defects, and neurodegeneration.When she is not in the lab, Jillian is forming new synapses by rock climbing throughout Southern California.

Jillian L. Shaw

View posts by Jillian L. Shaw
Jillian decided to dedicate herself to a life of exploring the mysteries of the brain after reading neurological case studies by Oliver Sachs and Ramachandran as a student at Vassar College. After completing a B.A. in Neuroscience with honors in 2009, Jillian headed to USC to pursue a Ph.D. in Neuroscience where she is now in her 5th year. A research stint in Belgium exposed Jillian to the complexities of cell signaling pathways, and her interests shifted from cognitive neuroscience to cellular and molecular neuroscience. Her current research focuses on the link between Down syndrome and Alzheimer’s disease using Drosophila as a genetic model to explore axonal transport, mitochondria dysfunction, synaptic defects, and neurodegeneration. When she is not in the lab, Jillian is forming new synapses by rock climbing throughout Southern California.

3 Comments

  1. This is a very good article you wrote, especially because there are still many Christians who believe that this mental challenge is a form of demon possession which completely un-nerves me. This disorder of the mind is so cruel to a person and to add the cruelty of societial beliefs is the worst type of psychological fear and failure a person could recieve. Education such as you present should be mainstream to help break down healthy peoples misguided perceptions of what paranoid schizophrenia is and just be kind. Society is always trying to put those who are different in a box and force them to be as themselves…so who are truly the crazies? I believe those that deal with unfamthomable inner tortures are the strongest of hearts because they learn how to cope in unbareable circumstance.

  2. My dad has this disorder and to me it is as though he is living inside of a scary nightmare wide awake. What is ironic is that he loves to sleep so he can dream. His dreams seems to give him devine direction. He has always followed this guidance he seems to get from God and has managed to be an asset to me later in life and to those around him despite his fears that in todays culture are becoming more and more realistic with the government storing all of our personal communicated information on computers. If I was 3 years old in today’s world being raised by my father, I would more certainly be convinced that what he was teaching me about life was indeed true. I feel for kids these days being raised by a parent with such delusions. It is very confusing to understand what is ture andwhat is not for them. Children need this education in schools so they can dechifer what is happening in their homes.

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