“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 . Synaptophysin is the most abundant synaptic vesicle protein and is capable of regulating endocytosis of synaptic vesicles both during and after sustained neuronal activity . Neurons communicate at contact sites called synapses. At pre-synaptic sites, neurotransmitter 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 synapse.
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.
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 system. 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.
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. Neuron 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.