March 22, 2016

March's featured paper is "Nonequivalent release sites govern synaptic depression," published in PNAS Proceedings of the National Academy of Sciences. The paper is published by a team led by Drs. Hua Wen, Matthew McGinley, Gail Mandel, and Paul Brehm.

Our brains are constantly processing information, using a networked system neurons to send signals throughout the human body. Information flows from one neuron to another across a synapse, a small gap across which neurotransmitters travel to propagate the signal. Research has shown that these connections are quite flexible – they are able to change their strength, a process known as synaptic plasticity. Many scientists believe that synaptic plasticity is central the molecular mechanisms of learning and memory.

"Understanding synaptic plasticity is probably one of the fundamental challenges of neuroscience," said Mary Heinricher, Ph.D., associate dean for basic science in the OHSU School of Medicine. "How do neurons have the flexibility to change their responses based on behavioral priorities, physiological constraints or experience? I chose this month's featured paper because the research team addresses this question eloquently with surprising results."

Synaptic fatigue

Short-term synaptic plasticity acts on a timescale of tens of milliseconds to a few minutes, and can either strengthen or weaken a synapse. 

"Synaptic fatigue or depression reflects a decrease in neurotransmitter release during repetitive stimulation," explained Paul Brehm, Ph.D., senior scientist at the Vollum Institute. "This form of plasticity is common among synapses and is a subject of great interest to neuroscientists."

"Despite decades of study, however, the underlying mechanisms remain controversial," added Gail Mandel, Ph.D., senior scientist at the Vollum Institute.

Models for synaptic depression have become increasingly complicated in an effort to account for all potential features. "One feature that has made models complicated is the ability of a synapse to depress at low frequencies, yet remain responsive to high frequency stimulation without depressing to the point of total failure," said Dr. Brehm. "This requires that synaptic depression bear a highly non-linear dependence on stimulus frequency."

"Surprising mechanism"

In most models, this nonlinearity is proposed to result from differences in the synaptic vesicles. This 'vesicle centric' view posits that different pools of vesicles remain in different states of release. A readily releasable pool of vesicles is active at low frequencies, but can be quickly depleted during higher frequency stimulation. Once depleted, a more fatigue resistant pool of vesicles is recruited to maintain release for high frequency responsiveness. What exactly defines this proposed difference between these vesicle pools has never been established, but still forms the central thinking about synaptic depression. 

"Drs. Mandel and Brehm and colleagues used a well-defined neuromuscular synapse in zebrafish to tease out how the strength of a synaptic connection changed with activity," said Dr. Heinricher. "They were able to uncover a surprising mechanism that almost certainly underlies changes in synaptic strength in many parts of the nervous system."

"Our findings point to a newly described mechanism that can account for the non-linearity," said Dr. Brehm. 

"Instead of multiple pools of vesicles, we found heterogeneity in vesicle fusion sites that we term slow and fast release sites," he added. 

"Fast sites can reload and release vesicles on the millisecond time scale permitting synapses to follow ultra-high frequencies. Slow release sites have a refractory period for reloading and require seconds to recover. "These sites are the principal players in synaptic depression," said Dr. Mandel. 

Important new insights

What advantages do fast and slow zones provide? "The dual zones provide a broad dynamic range over which synaptic responses can be down modulated through depression without compromising the responsiveness to high frequency firing," explained Dr. Brehm. 

Defects in the release sites may provide important new insights into neuromuscular diseases. 

"In 2002 we identified a new form of myasthenic syndrome through study of a rapsyn deficient mutant line," said Dr. Mandel. "As with humans, the afflicted fish can only mount a few movements before use-dependent fatigue sets in."

"The likely basis of this fatigue in humans has never been identified until now," continued Dr. Brehm. "We have found, using this animal model, that fatigue results in large part from exaggerated synaptic depression, resulting from a reduced number of fast release sites. With only slow release sites available, repetitive movements are restricted to low frequency tasks. This is especially problematic to postural and limb muscle."

"As with all new ideas, our proposed model of distinct release zones calls for further testing," said Dr. Mandel. 

"For this purpose, we have developed both physiological and optical means to study the behavior of individual release zones using the advantages offered by zebrafish neuromuscular junction," concluded Dr. Brehm. 

Following a course of physiological study by the Brehm lab, the research will turn to the Mandel lab for molecular and biochemical analyses of the release machinery to identify the distinguishing features. 

Resources

• Read the paper
  
• Read about the Brehm lab
  
• Read about the Mandel lab
  

Citation

Nonequivalent release sites govern synaptic depression
Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):E378-86. doi: 10.1073/pnas.1523671113. Epub 2015 Dec 29.
Hua Wen, Matthew McGinley, Gail Mandel, and Paul Brehm

More Published Papers

Previous School of Medicine Papers of the Month

Recent OHSU published papers

Pictured above: Clockwise, starting top left, Matthew McGinley, Hua Wen, Paul Brehm, Gail Mandel